Control of programmed cell death by neurotransmitters and neuropeptides in the developing mammalian retina

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Progress in Retinal and Eye Research 24 (2005) 457–491 www.elsevier.com/locate/prer

Control of programmed cell death by neurotransmitters and neuropeptides in the developing mammalian retina Rafael Linden, Rodrigo A.P. Martins, Mariana S. Silveira Centro de Ciencias da Saude (CCS), Instituto de Biofı´sica da UFRJ, Cidade Universita´ria, bloco G, Rio de Janeiro 21949-900, Brazil

Abstract It has long been known that a barrage of signals from neighboring and connecting cells, as well as components of the extracellular matrix, control cell survival. Given the extensive repertoire of retinal neurotransmitters, neuromodulators and neurotrophic factors, and the exhuberant interconnectivity of retinal interneurons, it is likely that various classes of released neuroactive substances may be involved in the control of sensitivity to retinal cell death. The aim of this article is to review evidence that neurotransmitters and neuropeptides control the sensitivity to programmed cell death in the developing retina. Whereas the best understood mechanism of execution of cell death is that of caspase-mediated apoptosis, current evidence shows that not only there are many parallel pathways to apoptotic cell death, but non-apoptotic programs of execution of cell death are also available, and may be triggered either in isolation or combined with apoptosis. The experimental data show that many upstream signaling pathways can modulate cell death, including those dependent on the second messengers cAMP–PKA, calcium and nitric oxide. Evidence for anterograde neurotrophic control is provided by a variety of models of the central nervous system, and the data reviewed here indicate that an early function of certain neurotransmitters, such as glutamate and dopamine, as well as neuropeptides such as pituitary adenylyl cyclase-activating polypeptide and vasoactive intestinal peptide is the trophic support of cell populations in the developing retina. This may have implications both regarding the mechanisms of retinal organogenesis, as well as pathological conditions leading to retinal dystrophies and to dysfunctional cellular behavior. r 2004 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Control of programmed cell death within the developing retina: evidence for dependency on Signal transduction pathways affecting the sensitivity to cell death in the developing retina . Control of programmed cell death by retinal neurotransmitters . . . . . . . . . . . . . . . . . . . . . 4.1. Glutamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. g-Amino butyric acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Glycine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Dopamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Adrenergics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6. Serotonin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Corresponding author. Tel.: +55 21 25626553; fax: +55 21 22808193.

E-mail address: [email protected] (R. Linden). 1350-9462/$ - see front matter r 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.preteyeres.2004.10.001

............... cell–cell interactions ............... ............... ............... ............... ............... ............... ............... ...............

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4.7. 4.8.

Acetylcholine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Purines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.1. Adenosine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.2. ATP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Neuropeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Retinal neuropeptide systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.1. Substance P and other tachykinins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.2. Somatostatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.3. Neuropeptide Y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.4. Corticotrophin releasing factor and related peptides . . . . . . . . . . . . . . . . . . . . . 5.1.5. Angiotensin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.6. Opioid peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.7. Pituitary adenylyl cyclase-activating polypeptide and vasoactive intestinal peptide 5.2. Control of programmed cell death by neuropeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The subject of programmed cell death (PCD) attracts an ever increasing interest both in the context of neural development as well as disease. PCD is a major event of neurogenesis, and accounts for the loss of large numbers of developing nerve cells during normal embryogenesis in all classes of vertebrates (Oppenheim, 1991, for review). This appears to have major consequences both for the quantitative matching of interconnecting neuronal populations, as well as for the correct wiring of neural pathways (Rager and Rager, 1979; Clarke, 1981). On the other hand, neurological diseases often lead to the loss of variable numbers of nerve cells and, in many instances, poor understanding of the distal causes as well as the intrinsic mechanisms of cell death preclude effective medical treatment (BertoliAvella et al., 2004). The retina displays both the developmental and the pathological scenarios of PCD. For some retinal cell types, unequivocal evidence has been gathered of developmental cell loss, although this is by no means certain for every cell class, and may vary among distinct vertebrate species (Linden and Reese, 2005, for a review). In turn, several retinal dystrophies have been both characterized as to the course and affected cell types (Pacione et al., 2003; Zarbin, 2004), as well as traced to inherited patterns and specific genes (Daiger, 2004). For several years, apoptosis was the exclusive focus of attention regarding both naturally occurring and pathological PCD in almost every field of Biology (Sloviter, 2002). It appeared that targeting of either the death-receptor or the mitochondrial, execution pathways of caspase-mediated apoptosis, would lead to universal experimental or therapeutic approaches to PCD. The rapid pace with which mechanisms of apoptosis were unveiled in the nineties, led to the

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impression that perhaps the mitochondrial pathway of apoptosis alone would explain how nerve cells die (Lossi and Merighi, 2003). This idea is probably too naı¨ ve. Recent studies support the view that apoptosis is but one form of PCD that may, alas, be executed by a variety of pathways. In addition to apoptosis, evidence has mounted for autophagic, and even necrotic execution mechanisms that fit the criterion of PCD (Bursch, 2001; Proskuryakov et al., 2003). Studies of non-apoptotic cell death have already defined a number of new targets for pharmacological or genetic intervention, and the growing literature in the field expands the notion that a network of pathways is available for PCD (Leist and Jaattela, 2001; Lockshin and Zakeri, 2001, 2002; Guimara˜es and Linden, 2004, for reviews). Recent work added demonstrations that hallmarks of apoptosis such as caspases may regulate both autophagy (Yu et al., 2004) and programmed necrosis (Vercammen et al., 1998), while typical autophagic processes may in turn regulate apoptotic execution pathways (Xue et al., 1999; Guimara˜es et al., 2003). The available data support the contention that cell death programs are interchangeable, and that interfering with one pathway may favor alternative execution pathways. This implies renewed interest in upstream controls of cell death, including both the search for early intracellular events that follow cell stress or damage (e.g. Matsuyama et al., 2000; Makin et al., 2001; Konishi et al., 2003; Petrs-Silva et al., 2004), as well as a tissue biology approach, with emphasis on cell–cell interactions that modulate the sensitivity to PCD. The aim of this article is to review evidence that neurotransmitters and neuropeptides control the sensitivity to PCD in the developing retina. Emphasis shall be placed upon the roles of extrinsic modulators of cell death and their signal transduction pathways, rather than on intracellular execution mechanisms. Adding to

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the well documented roles of neurotrophic factors upon neuronal survival (Barbacid, 1995; Huang and Reichardt, 2001; Miller and Kaplan, 2001; Bennet et al., 2002; Davies, 2003), small neuroactive molecules and peptides are likely mediators of the links between neural function and tissue maintenance. The roles of extracellular signaling molecules upon cell death highlight the fact that the survival of developing neurons is controlled by properties defined by the structure, maturation and physiological state of their tissue environment.

2. Control of programmed cell death within the developing retina: evidence for dependency on cell–cell interactions Studies of PCD, particularly apoptosis, usually place emphasis on the cell-autonomous nature of the mechanisms of cell demise (Green and Reed, 1998; Hengartner, 2000; Ravagnan et al., 2002). Nonetheless, it has long been known that a barrage of signals from neighboring and connecting cells, as well as components of the extracellular matrix (ECM) control cell survival (Raff, 1992). In the nervous system, early evidence for extrinsic control of cell death arose from experiments destined to test the hypothesis of competitive interactions in neural development (Hamburger, 1975; Prestige and Willshaw, 1975; Pilar et al., 1980; Linden, 1994, for review). Many studies supported the notion that competitive interactions among either developing axons or dendrites regulate PCD in the retina. In general, those studies were directed at ganglion cells and based on experiments in which either the removal of one eye favor the survival of neurons from the other eye projecting to the same terminal fields, or the removal of retinal ganglion cells favor the survival of neighboring cells with overlapping or abutting dendritic fields (Sengelaub and Finlay, 1981; Jeffery and Perry, 1981; Thompson et al., 1995; Hughes and McLoon, 1979; Boydston and Sohal, 1979; Carpenter et al., 1986; Vanselow et al., 1990; Perry and Linden, 1982; Linden and Perry, 1982; Linden and Serfaty, 1985; Linden, 1987, 1992, 1993). The evidence for competitive interactions implies that the survival of developing neurons depends either on a limited supply or limited access to neurotrophic support. Evidence was soon gathered for the promotion of ganglion cell survival by macromolecules produced both by the targets of the retinofugal axons, as well as within the retina itself (Schulz et al., 1990; Araujo and Linden, 1993; Ary-Pires et al., 1997), and the roles of neurotrophic factors in retinal cell survival are under close scrutiny (Bahr, 2000; Chaum, 2003, for reviews). Whereas the original neurotrophic theory had focused attention upon the role of axonal targets and retrograde

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trophic effects in the control of neuronal survival (Oppenheim, 1989), there is compelling evidence for anterograde neurotrophic support. A number of studies demonstrated that deafferentation increases cell death in target neuronal populations within the period of naturally occurring cell death (Cunningham et al., 1981; Giordano and Cunningham, 1982; Linden and Perry, 1983; Okado and Oppenheim, 1984; Clarke, 1985; Furber et al., 1987; Clarke and Egloff, 1988), and that neuron numbers in target nuclei are under control of their afferents (Linden and Renteria, 1988). Hypotheses raised to explain anterograde trophic control include contact-mediated cell interactions, activity-dependent processes mediated by neurotransmitters or neuromodulators, and the involvement of neurotrophic factors (Linden, 1994). Subsequent studies have shown unequivocally that certain neurotrophic factors are transported anterogradely and released by axon terminals, with trophic effects upon their target cells (von Bartheld et al., 1996, 2001; Fawcett et al., 1998; Spalding et al., 2002; Caleo et al., 2000, 2003; Caleo and Cenni, 2004). In turn, a role for neurotransmitters in cell survival was supported by early work showing the loss of autonomic ganglionic neurons following blockade of cholinergic receptors (Wright, 1981; Meriney et al., 1987; Maderdrut et al., 1988). Anterograde neurotrophic support depends on electrical activity in the afferent axons (Catsicas et al., 1992), which regulates the extracellular levels of both neurotrophins (Schinder and Poo, 2000), as well as of neurotransmitters and neuropeptides (Raiteri et al., 1993; Branchaw et al., 1998; Waterman, 2000). However, the role of intraretinal electrical activity is still controversial. Developing ganglion cells in vitro are either killed by blockade of voltage-gated sodium channels with tetrodotoxin (TTX) (Lipton, 1986), or, conversely, protected by the depolarizing agent veratridine (Pereira and Araujo, 1997). In vivo, however, blockade of electrical activity in the retina affected either the pattern (Fawcett et al., 1984; Jeyarasasingam et al., 1998) or the timing (Kobayashi, 1993), but not the extent of ganglion cell death (O’Leary et al., 1986; Scheetz et al., 1995). It is not known whether the sodium-dependent currents relevant for ganglion cell survival belong to either the ganglion cells themselves, or to retinal interneurons (Yamada et al., 2002; Steffen et al., 2003). Indeed, sodium channeldependent action potentials are not required for the release of certain neuroactive substances within the retina (Protti et al., 1997; Morgans, 2000). Thus, evidence for a role of neural activity upon developmental cell death in the retina is limited, and the issue deserves more attention. Although the results of competition experiments have been usually interpreted in terms of interactions of

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developing neurons, non-neuronal cell types also affect neuronal survival. Evidence is available that glial cells support the survival of retinal cells in vitro (Garcia et al., 2002, and references therein), but there is remarkably little evidence for such a role in vivo (DuboisDauphin et al., 2000; Molthagen et al., 1996; Li et al., 2001). In contrast, the retinal pigment epithelium (RPE) has been shown to play a role in the control of developmental cell death among both photoreceptors and retinal progenitor cells (Sheedlo et al., 1998, 2001; Soderpalm et al., 1999). Components of the ECM, such as laminin (Libby et al., 1999; Zhang et al., 2003), heparan sulfate (Erlich et al., 2003) and target-derived proteoglycans (Schulz et al., 1990; Huxlin et al., 1995) may also affect PCD in the developing retina. Mechanisms of ECM regulation may include the modulation of growth factors or cytokines (Sasisekharan et al., 1997; Schonherr and Hausser, 2000). The relevance of tissue structure to the control of developmental cell death is further highlighted by the evidence that gap junctions mediate the transfer of pro-apoptotic signals among developing retinal cells (Linden, 2000; Cusato et al., 2003). The intricate organization of the retina allows for cooperation of multiple cell types and tissue structures in the control of PCD. It is known, for example, that removal of ganglion cells induced by optic axon damage has limited effects upon developmental cell death in the inner nuclear layer (INL) (Perry and Linden, 1982; Osborne and Perry, 1985; Beazley et al., 1987; Williams et al., 2001; Cusato et al., 2001). This is consistent with multiple sources of trophic support for retinal interneurons, mediated both by their post-synaptic ganglion cells and by local interactions with other retinal cells, and modulated by the ECM and gap junctions. As part of the network of interactions of retinal cells with their environment, neurotransmitters and neuromodulators are likely to play a role in the control of developmental neuron death. It is noteworthy that massive cell death precedes the development of mature synapses (Cusato et al., 2001), and may include transient interactions of retinal neurons that are not destined to maintain such associations in the mature tissue (Williams et al., 2001). Indeed, post-synaptic effects can be elicited by acetylcholine released by growth cones (Young and Poo, 1983), which supports the hypothesis that neurotransmitters may affect neural development preceding the maturation of synaptic morphology and function. Furthermore, given the extensive repertoire of retinal neurotransmitters, neuromodulators and neurotrophic factors, and the exhuberant interconnectivity of retinal interneurons, it is likely that distinct classes of released neuroactive substances, such as neurotransmitters and neurotrophic factors, may interact.

3. Signal transduction pathways affecting the sensitivity to cell death in the developing retina Neurotrophic factor signaling has been thoroughly studied, and several pathways were found to be engaged by the binding of neurotrophins to their high- or lowaffinity plasma membrane receptors. The high-affinity tropomyosin receptor kinase (Trk) receptors mediate the survival-promoting actions of nerve growth factor (NGF)-family factors (Patapoutian and Reichardt, 2001; Beck et al., 2004), whereas the low-affinity panneurotrophin p75 receptor has emerged as a dual action transducer, which is able to play either an ancillary role to Trk receptor functions, or mediate pro-apoptotic signals upon binding of either NGF or other ligands (Huang and Reichardt, 2003; Teng and Hempstead, 2004). The cytoprotective actions of engaging Trk receptors with their cognate ligands are mediated by downstream pathways involving MAP kinases, PI3-kinase and PLC-g, as well as a variety of small soluble G proteins (Huang and Reichardt, 2003). Pathways downstream of p75 is less well understood, and appears to involve the small GTP binding protein Rac, the transcription factor NFkB and the stress-activated kinase JNK (Gentry et al., 2004). Signaling pathways engaged by neurotrophic factors in the retina have been recently reviewed (Bahr, 2000; Chaum, 2003), and the reader is referred to those articles for further details. Receptors for small neuroactive molecules are, however, distinct from those for neurotrophins. Neurotransmitters engage either ionotropic receptors structurally linked to ion channels, or G-proteincoupled receptors (GPCRs) (Cooper et al., 2002), and the latter is the rule among neuropeptide receptors (McCulloch et al., 2002; Lahlou et al., 2004; Chen et al., 2004; Bodnar, 2004). GPCR may then activate a variety of downstream intracellular signaling pathways (Cooper et al., 2002; Moldrich and Beart, 2003; Liebmann, 2004), several of which have been shown to affect the sensitivity to PCD, often in contradictory ways (McConkey and Orrenius, 1994; Blatt and Glick, 2001; Verkhratsky and Toescu, 2003). Signaling pathways have often been examined independent of their originating extracellular modulators, and this is the subject of the present section. Among intracellular messengers induced by either ionotropic or metabotropic receptors, calcium (Muller and Koch, 1998; Fain and Lisman, 1999; Krizaj and Copenhagen, 2002), nitric oxide (Roth, 1997; Neufeld et al., 1999; Naskar and Dreyer, 2001) and cyclic adenosine 30 50 -monophosphate (cAMP) (Strauss et al., 1998; Kaupp and Seifert, 2002) have been implicated in retinal cell survival and degeneration. Most such studies concern retinal dystrophies or adult animal models, and little is known of the roles of second messengers upon

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the control of PCD following activation of membrane receptors, particularly in the developing retina. Modulation of intracellular calcium affects the sensitivity to cell death in developing retinal tissue (Linden et al., 1996, 1999). Treating retinal explants with thapsigargin, an inhibitor of the sarco/endoplasmic reticulum calcium ATPase, induced apoptotic cell death preferentially among photoreceptors (Chiarini et al., 2000, 2003; Silveira et al., 2002), although the time course of cell death in axotomized ganglion cells is also altered by the same compound (Petrs-Silva et al., 2004). Time-lapse video microscopy of ganglion cells undergoing apoptosis in the neonatal rat retina in vitro, revealed a progressive increase of intracellular calcium accompanying the sequence of cytomorphological changes (Cellerino et al., 2000). It is, however, still unclear whether the modulation of calcium levels in this case is a necessary step for the death of these neurons, or whether the changes correspond to a general deregulation of the intracellular calcium buffering systems, as death proceeds to its end. It should be noted that despite the apparent consensus that calcium is the key mediator of excitotoxicity (Choi, 1988, 1994; Ferreira et al., 1996; Burgos et al., 2000; Calzada et al., 2002; Arundine and Tymianski, 2003), evidence in the retina is somewhat controversial, and both the role of calcium in glutamate neurotoxicity (Olney et al., 1986; Chen et al., 1998), as well as the coupling of neuroexcitation and neurotoxicity (Shen and Slaughter, 2002) have been called into question. In turn, limited evidence is available of calcium-mediated neuroprotection in the retina. In contrast with the neuroprotective role of depolarization-induced calcium entry demonstrated in cerebellar or sympathetic neurons in vitro (Gallo et al., 1987; Xia et al., 2002), or in the auditory system in vivo (Miller et al., 2003), depolarization-induced retinal neuroprotection has been traced to the release of intracellular calcium stores (Fernandes Pereira and Araujo, 2000). Understanding the role of calcium in the control of retinal cell death will, therefore, require a thorough

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examination of the multiple calcium signals, variable compartmentalization and the many possible pathways of regulation, inclusive of neurotransmitter receptor activation (Orrenius et al., 2003). This adds to the dual pro- and anti-degenerative roles demonstrated for calcium (Verkhratsky and Toescu, 2003). A particular aspect of calcium signaling that also deserves attention is the occurrence of spontaneous calcium waves coordinated across both differentiated inner layers and the proliferative zone of the developing retina (Catsicas et al., 1998; Syed et al., 2004), which, nonetheless, have yet to be tested for a role upon PCD. Nitric oxide (NO) is produced by both neurons and glia, and the exact physiological roles of this messenger from either source are still a matter of debate. Nitric oxide has been a subject of particular interest in the context of neurodegeneration, but dual degenerative/ protective effects of NO have been reported in the nervous system (Dawson et al., 1992; Jaffrey and Snyder, 1995; Dawson and Dawson, 1998; Kara and Friedlander, 1998; Klocker et al., 1998; Fiscus, 2002; Contestabile et al., 2003). Both effects have also been detected upon retinal cells, although the evidence is somewhat contradictory. For example, distinct from the chick retina, in which the activity of nitric oxide synthase is the highest in early stages of development (Paes-de-Carvalho and Mattos, 1996), it was reported that nitric oxide synthase did not appear within the rat retina until the second postnatal week (Patel et al., 1997), suggesting that the NOgenerating enzyme was unlikely to play a major role in normal physiological retinal ganglion cell death, which is completed at most at around postnatal day 10 (Perry et al., 1983), nor upon axotomy-induced cell death (Patel et al., 1997). Subsequent work, however, showed evidence for functional NO synthase activity in the newborn rat retina, and nitric oxide as well as both the substrate L-arginine and a cofactor of NO synthase, had protective effects upon undifferentiated post-mitotic retinal cells (Fig. 1). The data indicated that NO produced by amacrine and ganglion cells is a paracrine

Fig. 1. Neuroprotection by nitric oxide in the developing retina. Apoptotic cells (arrows) were detected in the NBL of newborn rat retinas by immunohistochemistry to activated caspase-3. Retinal explants were incubated for 24 h in control medium (A), with 1 mg/ml anisomycin (B), or with anisomycin plus 10 mM of the nitric oxide donor S-nitroso-acetyl-penniciline (C). Modified from Guimara˜es et al. (2001).

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modulator of cell death within the retinal tissue, and that these effects are partly mediated by soluble guanylyl cyclase (Guimara˜es et al., 2001). In contrast, L-arginine was reported to induce apoptosis in the retina of slightly older rat pups (Kim et al., 2002). Nitric oxide is a well-known product of activation of receptors for excitotoxic amino acids (EAA) (Contestabile, 2000), in keeping with the hypothesis that NO mediates excitotoxicity (Strijbos, 1998). However, it was shown that in the chick embryonic retina, nitric oxide links EAA receptor activation to cGMP formation, but this pathway does not appear to play a role in excitotoxicity (Zeevalk and Nicklas, 1994). It was also shown that in newborn rabbits, the EAA-induced nitric oxide-mediated excitotoxic pathway may not be active, because NO synthasecontaining cells can only be detected in their mature configuration at later stages (Haberecht et al., 1997). Neurodegenerative or neuroprotective effects of nitric oxide may, in addition, depend on the redox state of the NO group (Lipton, 1999), on the oxidative state of the cell (Chiueh, 1999; Estevez and Jordan, 2002), on the activity of the NO-synthetic pathway and the distance between the source and the putative target molecules, as well as on intervening chemical reactions (Beckman and Koppenol, 1996; Lancaster, 1997; Laurent et al., 1996; Vaughn et al., 1998; Denicola et al., 2002). These factors, together with the evidence reviewed above that the effects of nitric oxide may vary at distinct stages of development, complicate the task of defining the roles of neurotransmitter-induced NO upon developmental cell death, as compared with an apparently clearer picture in other aspects of neural function (Hawkins et al., 1998; Daniel et al., 1998; Blottner, 1999; Prast and Philippu, 2001; Toda and Okamura, 2003; Blackshaw et al., 2003; Stern, 2004). The second messenger cAMP has been thoroughly studied in the context of PCD (reviewed by Silveira and Linden, 2004). Increased concentrations of cAMP have been shown to either induce or prevent cell death in a variety of cell types, including neuron-like PC12 cells (Silveira and Linden, 2004, for review and references). Experimental approaches based on the use of either forskolin or cell-permeant analogs, such as db-cAMP, 8-Br-cAMP and chlorophenylthio-cAMP, as well as isobutyl-methyl-xantine (IBMX), that blocks the degradation of cAMP, provided compelling evidence for neuroprotective effects of cAMP upon TTX-treated dissociated cell cultures from the spinal cord and dorsal root ganglion (DRG), NGF-deprived sympathetic, sensory and septal neurons, mesencephalic dopaminergic neurons exposed to the toxin 1-methyl-4-phenylpyridinium ion (MPP+), cerebellar granule neurons in low potassium medium, and dissociated cerebral cortical neurons subject to high concentrations of glutamate (Brenneman et al., 1985, 1987; Rydel and Greene, 1988;

Edwards et al., 1991; Hartikka et al., 1992; Morio et al., 1996; Kew et al., 1996; Chang et al., 1996; Chang and Korolev, 1997). In dissociated cell cultures of postnatal rat retina, 8-Br-cAMP prevented the death of retinal cells induced either by TTX or by high concentrations of glutamate (Kaiser and Lipton, 1990; Shoge et al., 1998). In cultures of purified retinal ganglion cells, an increase in intracellular cAMP was required for responsiveness to various trophic factors (Meyer-Franke et al., 1995), while forskolin plus IBMX alone were sufficient to protect cultures of highly purified spinal motor neurons in vitro, with a potency that could only be matched by combinations of more than five trophic factors (Hanson et al., 1998). The latter studies provided evidence for distinct requirements of intracellular cAMP for the survival of various neuron types, but may be dependent on peculiar conditions of either the dissociated or the purified neuron cultures. We have studied the effects of cAMP upon the sensitivity to cell death in histotypical explants made of the retina of neonatal rodents (Linden et al., 1999). In this preparation, the protein synthesis inhibitor anisomycin induces apoptosis of undifferentiated post-mitotic cells, within the neuroblastic (ventricular) layer (NBL) (Rehen et al., 1996, 1999). Cell death in the NBL was blocked by concurrent incubation of the explants with any one of the following drugs that increase cAMP: forskolin, 8-Br-cAMP, IBMX and the cAMP-phosphodiesterase specific inhibitor 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro-201724), whereas the cGMP-phosphodiesterase inhibitor 1,4-dihydro5-(2-propoxyphenyl)-7H-1,2,3-triazolo[4,5-d]pyrimidine7-one (Zaprinast) had no effect. These data strongly supported the hypothesis that cAMP has a neuroprotective role within the developing retina, and the protective effect of the phosphodiesterase inhibitors alone indicated that endogenous neuroactive molecules that signal through cAMP are involved (Varella et al., 1997). Further studies showed that, while cell death induced in proliferating photoreceptor precursor cells by the topoisomerase II inhibitor etoposide was insensitive to forskolin, the activation of adenylyl-cyclase prevented cell death of differentiating photoreceptors induced by thapsigargin (Fig. 2). These data suggest that the neurotrophic response of retinal cells to cAMP is developmentally regulated (Chiarini et al., 2003). In contrast with either TTX-induced cell death in clusters of retinal cells following dissociation (Kaiser and Lipton, 1990), or with the death of purified retinal ganglion cells (Meyer-Franke et al., 1995), forskolin alone failed to prevent the retrograde degeneration of axotomized ganglion cells in free-floating retinal explants (Rehen et al., 1996). The reason for this discrepancy is not known. However, it was shown that TTX-induced electrical blockade leads to a decrease in

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Fig. 2. Developmentally regulated control of PCD by cAMP. The diagram represents three stages in the development of retinal photoreceptors in the rat: from left to right proliferating precursors, undifferentiated post-mitotic cells and differentiating, rhodopsin-expressing photoreceptors. The histograms show the frequency of dead cells in retinal explants treated for 24 h in various combinations of control medium (CTR), 10 mM forskolion (FK), 2 mM etoposide (ETO) or 10 nM thapsigargin (THP). Modified from Chiarini et al. (2003).

intracellular cAMP (Brenneman et al., 1985; Kaiser and Lipton, 1990), which raises the hypothesis that ganglion cells may sustain higher concentrations of cAMP in explants than in dissociated cell cultures due to synaptic action of growing afferent inputs (Young and Poo, 1983), which form rudimentary synaptic structures at early postnatal stages (Fernandes et al., 1988). This synaptic input, in turn, could obviate the need for either depolarization or cAMP as ancillary survival factors for the axotomized ganglion cells (Meyer-Franke et al., 1998). Further understanding of the roles of second messengers upon PCD depends on the identification of downstream pathways. Among known second messengers, calcium probably holds the greatest number of possible downstream effectors. For many of these, such as the protein phosphatase calcineurin, NO synthase, endonucleases, phospholipases, transglutaminase and proteases such as calpain, there is at least some evidence of a role in the control of PCD (Orrenius et al., 2003). In addition, the central role of calcium in endoplasmic reticulum stress responses has been highlighted (Verkhratsky and Toescu, 2003; Orrenius et al., 2003), particularly with respect to the triggering of the ER

stress-induced, caspase-12-mediated apoptotic pathway (Nakagawa et al., 2000). Effects of nitric oxide have been traced downstream to activation of soluble guanylyl cyclase, direct nitrosylation of cellular targets or to combination with reactive oxygen species (reviewed in Guimara˜es et al., 2001). Other identified effectors include the tumor suppressor genes p53 and Rb, and the cyclin-dependent kinase inhibitor p21 (Gibbs, 2003), all of which have been implicated in PCD. Targets of cAMP include the cAMP-dependent protein kinase (PKA), nucleotide-gated membrane channels and certain GTP-exchange factors (GEFs). The Erk MAP kinase pathway has also been shown to be target of cross-modulation by cAMP (reviewed in Silveira and Linden, 2004). Downstream phosphorylation of residues Ser112 and Ser155 of the pro-apoptotic Bcl-2 family protein Bad have been traced to PKA, and constitute a major link between cAMP and the apoptotic execution machinery (Harada et al., 1999; Virdee et al., 2000; Lizcano et al., 2000). The transcription factor cAMP-responsive element binding protein (CREB), which is also a target of PKA among other protein kinases, is required for the survival of peripheral

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neurons (Lonze et al., 2002), mediates neurotrophic responses (Riccio et al., 1999), and regulates the expression of the neurotrophin receptor TrkB (Deogracias et al., 2004), but it is not clear whether the antiapoptotic effect of CREB is due to phosphorylation by PKA (Bonni et al., 1999). Non-specific cationic channels activated by cAMP are permeable to calcium, as well as to sodium and potassium (Goulding et al., 1992) and could conceivably affect cell death pathways (Xiao et al., 2002; Orrenius et al., 2003). However, there is currently no evidence for a link between these channels and PCD. Finally, modulation of GEFs may affect the Erk MAP kinase pathway through the activity of both Rap1 and Ras (Rooji et al., 1998; Kawasaki et al., 1998; Pham et al., 2000), but evidence for a role of this pathway in the control of cell death is also lacking. Current evidence, therefore, favors the interpretation that, rather than a transcription-mediated process, the PKA-mediated phosphorylation of Bad is the most likely downstream target of cAMP related to the modulation of PCD (Silveira and Linden, 2004). Other signaling pathways have been implicated in the control of PCD in the retina. For example, the nonselective protein kinase inhibitor 2-aminopurine prevented apoptosis of axotomized ganglion cells and induced apoptosis in the NBL of explants of the neonatal rat retina (Varella et al., 1997). This drug inhibits a variety of kinases, but does not have significant effects upon either PKA or protein kinase C (see Varella et al., 1997, for references). In turn, evidence was reported that the survival of retinal ganglion cells in dissociated cell cultures of the neonatal rat retina may be mediated by a mechanism that involves PKC activation (dos Santos and de Araujo, 2000). It is not known whether this pathway is engaged by neurotransmitters or neuropeptides, but PKC was shown to mediate proliferative responses to extracellular ATP in developing retinal cells in culture (Sanches et al., 2002). In retrospect, current understanding of signal transduction might have led to the prediction that the experimental modulation of signaling pathways in a whole-cell scale, and out of context with respect to their extracellular modulators would yield controversial results. Recent progress, particularly in the development of tools for the detection of localized transients of calcium and other signaling molecules, strongly support the concept that metabolic regulation is highly compartmentalized (Pani et al., 2001; Petersen, 2002; Verkhratsky, 2002; Sayer, 2002; Orrenius et al., 2003; Gonzalez-Gaitan, 2003; Weijer, 2003; Suarez, 2003; Pfeilschifter et al., 2003; Paschen, 2003; Tasken and Aandahl, 2004). This principle applies equally well to PCD, of which certain pathways have been traced to specific organelles, and subcellular translocation of effector molecules has a central role. Compartmentali-

zation of intracellular responses depends on the distribution, density and possible interactions of membrane receptors for extracellular signaling molecules. Therefore, understanding the roles of calcium, nitric oxide and cAMP in the control of PCD in the developing retina requires an integrated analysis of their natural modulators. Among these, neurotransmitters and neuropeptides occupy a prominent role, since they are major driving forces of signaling pathways within the retina.

4. Control of programmed cell death by retinal neurotransmitters Processing of visual information in the mature retina involves various neurotransmitter systems. The amino acid glutamate is the neurotransmitter used in the radial pathway of adult retina (Massey, 1991; Barnstable, 1993). This pathway mediates signaling from photoreceptors through bipolar cells to the ganglion cells. Both amacrine and horizontal cells are also endowed with glutamate receptors. The latter cell types may show distinct neurotransmitter phenotypes. Amacrine cells may release acetylcholine, dopamine, GABA, glycine, serotonin and adrenalin (Hayden et al., 1980; Masland et al., 1984; Voigt, 1986; Djamgoz and Wagner, 1992; Ehinger, 1982; Witkovsky and Schutte, 1991; Mosinger et al., 1986; Davanger et al., 1991; Pourcho and Goebel, 1987; Brunken et al., 1993; Vaney, 1986; Hadjiconstantinou et al., 1983) and horizontal cells may release GABA and acetylcholine (Calaza et al., 2003; Jellali et al., 2002; Kim et al., 1998). Many of the neurotransmitter systems expressed in the adult retina are already present in the developing tissue (see Kalloniatis and Tomisich, 1999; Feller, 2002, for reviews). It has long been established that neurotransmitters regulate retinal development. Many studies demonstrated that functional neurotransmitter receptors mediate complex functions in the developing CNS, including the retina, even before the onset of synaptic-mediated neurotransmission (see Lankford et al., 1988; Komuro and Rakic, 1993; Lipton and Kater, 1989; Cameron et al., 1998; Nguyen et al., 2001, for review). Early during retinal development, retinal cells display spontaneous electrical activity, and in particular ganglion cells fire periodical action potentials (Galli and Maffei, 1988). This pattern of retinal waves was shown to depend on the activation of the nicotinic subtype of acetylcholine receptors (nAChR) (see Feller, 2002, for review), which is expressed in early stages of retinal development (Zhou, 2001). Exactly how this modulates retinal development is still under investigation. Regulation of neuroblast proliferation mediated by both cholinergic and purinergic neurotransmitter receptors was also demonstrated during early stages of retinal development

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in the chick embryo (Pearson et al., 2002). Altogether, these observations imply that developing retinal cells have functional receptors for distinct neurotransmitters, and that the signaling pathways activated by these transmitters may affect developing retinal cells in multiple ways. In keeping with evidence that neurotransmitter release may precede the establishment of mature synapses (Young and Poo, 1983), a calcium-independent, nonvesicular mechanism of GABA and glutamate release in hippocampal CA1 neurons was found during embryonic and postnatal development (Demarque et al., 2002). Whether this developmentally regulated type of neuronal communication functions in the developing retina is still unknown. It is, however, noteworthy, that immunoreactivity for both the vesicular glutamate transporter, VGLUT1, as well as the vesicular GABA/glycine transporter, VGAT, was first detected during postnatal development in the retina (Johnson et al., 2003). Whether glutamate, GABA or glycine-mediated functions during rodent retinal embryonic development are mediated through a non-vesicular mechanism of neurotransmitter release is an intriguing possibility. The expression and distribution of neurotransmitter receptors and the evidence for regulation of cell death by neurotransmitters in the developing mammalian retina will be reviewed in turn. In each section, data obtained in other areas of either the central or peripheral nervous system will be referred to, when relevant to the points raised. 4.1. Glutamate Glutamate is well known as an excitotoxin in the central nervous system (see Choi, 1988, 1992; Michaelis, 1998; Nicholls et al., 1999; Duchen, 2000; Sattler and Tymianski, 2001, for review). The correlation between the excitatory and the toxic effects of glutamate upon neuronal cells led to the glutamatergic excitotoxicity theory, according to which glutamate-induced cell death is a consequence of excessive depolarization (excitation) of neuronal cells (Olney et al., 1971). Overactivation of glutamate receptors is thought of as a key cellular effector of neurotoxicity observed in various pathological situations, such as anoxic, hypoxic or ischemic insults, epilepsy, neurodegenerative diseases, diabetic retinopathy, retinal detachment and glaucoma (Lombardi et al., 1994; Matini et al., 1997; El Asrar et al., 1992; Smith, 2002; Sherry and Townes-Anderson, 2000; Barber, 2003; Lipton, 2003; Price, 1999; Nishizawa, 1999; McNamara, 1999). High levels of glutamate are found in several developing areas of the CNS, including the retina (Miranda-Contreras et al., 1998, 1999, 2000; Thorenson and Witkovsky, 1999). Both functional glutamate receptors and transporters are expressed early during

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vertebrate retinal development (Grunder et al., 2000; Hartveit et al., 1994; Sucher et al., 2003; Johnson et al., 2003; Sherry et al., 2003; Wong, 1995a; Allcorn et al., 1996). In fact, the pioneer studies describing glutamatergic toxicity were done in the retina (Lucas and Newhouse, 1957). Subsequently, many studies demonstrated glutamate-induced cell death in both the developing and adult retinal tissue. Some studies focused on the mechanisms of glutamate-induced cell death, while in others excitotoxic cell death was used as a tool for the study of various neuroprotective agents (Volonte and Merlo, 1996; Lima et al., 2003; Ferreira and Paes-deCarvalho, 2001; Zacco et al., 2003; Wehrwein et al., 2004; Khaspekov et al., 2004). In this section, only studies directly related to either induction or protection from cell death by glutamate will be reviewed. Glutamate-induced cell death can be triggered in both the adult and developing retina (Ferreira et al., 1996; Haberecht et al., 1997; Rocha et al., 1999; Zhang et al., 2000a, b). During development, high concentrations of glutamate kill preferentially cells in the inner retina, within the region occupied by amacrine cells, as opposed to the proliferative NBL (Rocha et al., 1999). This pattern correlates with the expression of glutamatergic receptors during early retinal development, suggesting that glutamate may selectively kill inner retinal cells at that stage because of the restricted pattern of expression of its receptors (Grunder et al., 2000). In fact, we found that the toxic effect of glutamate in the adult rat retina spreads to other retinal cellular layers, and such pattern is similar to that of expression of the glutamate receptors (Rocha et al., 1999). Interestingly, it was demonstrated that, in the retina, glutamate-induced cell death may occur either through either NMDA or non-NMDA receptor subtypes. Several studies demonstrated that direct activation of non-NMDA receptors can induce cell death in developing rat and chick retinas (Duarte et al., 1998; Chen et al., 1998; dos Santos et al., 2001). In turn, we found that the toxic effects of glutamate upon developing and adult rat retina occurs specifically through NMDA receptors (Rocha et al., 1999). Since in the latter study, we did not test for possible toxic effects of high concentrations of non-NMDA receptors agonists, it is unclear whether the different results in distinct studies may be a consequence of the species (rat vs. chick) or type of culture (retinal explants vs. dissociated retinal cells) examined. An additional factor may the differential sensitivity to NMDA-induced toxicity in distinct retinal cell types. Purified ganglion cells expressing functional NMDA receptors were found to be insensitive to acute NMDA- or glutamate-induced toxicity, whereas amacrine cells were highly sensitive to that insult (Ullian et al., 2004). This suggests that molecular mechanisms downstream of receptor signaling may determine the sensitivity to glutamate-induced cell death.

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Although the molecular basis of glutamate toxicity is not completely defined, abundant data favor that it depends on Ca2+ in neuronal cells (Choi, 1985, 1987, 1995, 1998; Rothman et al., 1987; see Sattler and Tymianski, 2000, for review). In the retina, however, the ionic mechanisms involved in glutamate excitotoxicity are somewhat controversial. Cell death induced by either glutamate or its agonists was shown to depend on calcium influx into chick embryonic retinal cells (Ferreira et al., 1996). In contrast, evidence also has been gathered for a calcium-independent mechanism of glutamate toxicity in the retina. Thus, cell death induced by kainate was demonstrated independent of extracellular calcium, but dependent on extracellular chloride and sodium (Zeevalk et al., 1989; Chen et al., 1998). Interestingly, it was also shown that kainate and NMDA toxicity were partially blocked by the combined blockade of both GABA and glycine receptors, suggesting a cooperative role for these inhibitory neurotransmitters in glutamate-induced excitotoxicity within the retina (Chen et al., 1998). Downstream mechanisms are still unclear. Evidence was gathered in various areas of the CNS that glutamate-induced cell death depends on the activation of nitric oxide synthase (Geyer et al., 1995; Dawson and Dawson, 1998; Neufeld, 1999). This may also be the case in developing retina, because co-incubation with the nitric oxide synthase inhibitor L-NAME blocked glutamate-induced cell death in amacrine cells from cultured retinal explants (Guimara˜es et al., 1998). Toxic effects of NO upon ganglion cells were detected in the developing retina (Nichol et al., 1995), and coupling of glutamate receptors to NO synthesis was demonstrated in embryonic chick retina (Zeevalk and Nicklas, 1994; Lopez-Colome and Lopez, 2003). Nevertheless, high, non-physiological concentrations of glutamate resulted in blockade of NO production (Lopez-Colome and Lopez, 2003), and the nitric oxide synthase inhibitor NNA, did not inhibit NMDA-induced cell death in embryonic chick retina (Zeevalk and Nicklas, 1994). In addition, neuroprotection by nitric oxide has been demonstrated in developing retinal tissue (Guimara˜es et al., 2001). Thus, it is not clear whether the activity of NO synthase and the production of nitric oxide are required for glutamatergic toxicity in the developing retina. Evidence was reported for a role of the transcription factor p53 in glutamate-induced neuronal death (Morrison et al., 1996; Grilli and Memo, 1999; Uberti et al., 2000; Lakkaraju et al., 2001; Culmsee et al., 2001). In the adult mouse retina, increased expression of p53 followed in vivo treatment with NMDA, and heterozygous p53-deficient mice showed attenuated NMDAinduced cell death (Li et al., 2002). Increased expression of p53 and genetic evidence for a role of p53 in ischemiainduced cell death had also been reported in adult rat

retina (Rosenbaum et al., 1998; Joo et al., 1999). Evidence for a role of the p38 MAP kinase in glutamate-induced cell death was also gathered in many regions of the CNS (Kawasaki et al., 1997; Jeon et al., 2000; Chen et al., 2003; Rivera-Cervantes et al., 2004). However, despite the evidence that p38 has a role in axotomy-induced cell death of ganglion cells (Kikuchi et al., 2000), it is unclear whether this stress-activated kinase participates in the cell death signaling pathway induced by glutamate in the developing mammalian retina. Activation of caspase-3 was shown both in a model of NMDA-induced cell death in cortical cells in vitro and after a cerebral ischemic insult in vivo (Tenneti and Lipton, 2000; Namura et al., 1998). In both rat and rabbit adult retinas, glutamate receptor activation increased caspase-3 activity, and pharmacological inhibition of this protease activity blocked glutamatergic toxicity both in vitro and in vivo (Lam et al., 1999; Kwong and Lam, 2000; Chen et al., 2001). In cultures of developing chick retinal cells, NMDA receptor activation induced a transient increase in caspase-3 activity. Although dependence of caspase activity for the occurrence of cell death was not demonstrated, the data suggest a role for a caspase-dependent apoptotic machinery in NMDA-induced cell death in the developing retina as well (Ientile et al., 2001). In contrast with glutamate toxicity, evidence that this amino acid may also act as a trophic factor in the nervous system came from studies in the developing cerebellum. NMDA receptor activation maintained the survival of cerebellar granule cells both in vitro (Balazs et al., 1988a, b) and in vivo (Monti and Contestabile, 2000). Similar evidence was obtained in other regions of both PNS and CNS (Brenneman et al., 1990; Gould et al., 1994; Gould and Cameron, 1996). In early studies of the developing retina, agonists of glutamate metabotropic receptors were shown to protect cultured retinal cells (Siliprandi et al., 1992). Subsequent studies provided similar evidence that glutamate plays a protective role upon developing retinal cells, and implicated other subtypes of glutamate receptors in the neuroprotective effects (Nichol et al., 1995; Reuter and Zilles, 1993; Fix et al., 1995). We showed that chronic activation of NMDA receptors protects both differentiated and progenitor retinal cells against either glutamate- or irradiationinduced cell death, respectively. This effect was reverted by co-incubation with a soluble TrkB–IgG receptor (Rocha et al., 1999). In addition, the activation of NMDA receptors in retinal tissue leads to a specific increase in the expression of both BDNF and TrkB, but not NT-4 (Fig. 3). The data indicate that glutamatergic neuroprotection depends on the activation of native TrkB receptors, following an increase in both BDNF and its high-affinity receptor (Martins et al., 2004).

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Fig. 3. Neuroprotection by activation of the NMDA-type receptor for glutamate. (A) Rates of cell death in the developing amacrine cell layer of retinal explants from newborn rats, incubated for a total period of 24 h, and treated during the last 6 h either without (CTR) or with 6 mM glutamate (GLUT), after 18 h with either no pre-treatment (CTR and GLUT) or pre-treated with 60 mM glutamate (glut+GLUT) or 60 mM NMDA (NMDA+GLUT). (B) RNAse protection assay showing increased expression of BDNF following 18 h treatment with 100 mM NMDA, as compared with untreated retinal explants from newborn rats. (A) Modified from Rocha et al. (1999) and (B) from R.A.P. Martins et al. (unpublished data).

Recently, it was shown that glutamate receptor activation increases the expression of neurotrophins in purified cultures of Mu¨ller cells (Taylor et al., 2003), suggesting that glial cells may be at least part of the sources of neurotrophins produced in response to glutamate. Although these studies demonstrate that glutamate may act as a trophic factor in the developing retina, it is still unclear whether this effect applies to the control of naturally occurring cell death during retinal development. This has been, however, shown in developing cerebral cortex (Ikonomidou et al., 1999). In addition, the downstream signaling pathways engaged by glutamate-induced TrkB stimulation, and responsible for neuroprotection are likely to be similar to those induced by BDNF in other systems, but have not yet been addressed in the developing retina. 4.2. g-Amino butyric acid There is little evidence for regulation of cell death by GABA in the developing nervous system. Signaling through GABA-A receptors was shown to protect cultured striatal neurons (Ikeda et al., 1997). GABAmediated regulation of the neurotrophic factor BDNF was demonstrated in developing hippocampal and cortical cells (Berninger et al., 1995; Mantelas et al., 2003), suggesting a possible indirect pathway for GABA-induced neuroprotection. However, evidence is lacking that BDNF actually mediates effects of GABA on neuronal survival. Functional GABA receptors exist both in developing and adult mammalian retina (Rorig and Grantyn, 1993; Greferath et al., 1995; Huang and Redburn, 1996; Mitchell and Redburn, 1996; Karne et al., 1997; Hu

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et al., 1998; Mitchell et al., 1999; Koulen, 1999a, b; Greka et al.; 2000; Grunert, 2000; Wu and Cutting, 2001; Biedermann et al., 2004). GABA transporters were also described in developing rodent retina (Johnson et al., 2003). It is well established that during development GABA acts as an excitatory amino acid, in contrast with the classical inhibitory function found in mature synapses (see Ben Ari, 2002, for review). In view of both toxic and neuroprotective effects of the excitatory amino acid glutamate, as well as of the evidence for a functional role of GABA in retinal cell differentiation (de Mello, 1984; Spoerri, 1988; de Mello et al., 1991; Messersmith and Redburn, 1993; de Almeida et al., 2002), it is possible that GABA may interact with glutamate in excitotoxic effects. However, the timing of development of GABA and glutamatergic synapses is not coincident, and the only evidence for an excitotoxic role of GABA has been attributed to chloride currents (Chen et al., 1998) distinct from those that appear to mediate the early excitatory role of this amino acid (Ben Ari, 2002). 4.3. Glycine Limited evidence is also available for glycinergic effects upon cell death in the nervous system. Thus, it has been shown that both exogenous and glial-secreted glycine maintain the survival of cerebellar Purkinje cells in vitro (Furuya et al., 2000). Developing retina contains functional glycinergic receptors (Sassoe-Pognetto and Wassle, 1997; Young and Cepko, 2004). It was reported that the activation of glycine receptors by taurine regulates cell proliferation and photoreceptor maturation during development of the rodent retina (Young and Cepko, 2004). However, the same authors also showed that transfection-induced expression of glycinergic receptor GlyRa2 in cultured embryonic mouse retina, that normally does not express this receptor, did not alter the proportion of TUNEL-positive cells (Young and Cepko, 2004). To date, the only evidence for a role of glycine in the control of developmental retinal death is the reported cooperative effect exerted together with GABA upon glutamate excitotoxicity in the chick retina (Chen et al., 1998). 4.4. Dopamine Dopamine is present very early during rat retinal ontogenesis (Martin-Martinelli et al., 1989; Wu and Cepko, 1993). Tyrosine hydroxylase (TH)-immunoreactive (IR) cells were first detected in retinal whole mounts at embryonic day 19 (E19) (Wu and Cepko, 1993). Dopamine receptors are divided in two subfamilies, D1like (receptors D1 and D5) and D2-like (D2, D3 and D4). D1-like receptors are generally coupled to protein Gs, while D2-like receptors are usually coupled to Go or

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Gi proteins. The distribution of D1 receptor (D1R) immunoreactivity was investigated during postnatal development of the rat retina and this receptor was found already at birth (Koulen, 1999a, b). D2R in rat retinas is mainly associated with extrasynaptic membranes of dopaminergic cells, as well as in processes of non-dopaminergic amacrine cells. It was also suggested that D4R is expressed in photoreceptors (Derouiche and Asan, 1999). Dopamine is neurotoxic for various neuron types, such as cultured rat forebrain (Hoyt et al., 1997) and striatal neurons (Chapman et al., 1989; Cheng et al., 1996; Cyr et al., 2003), dissociated mesencephalic cells (Michel and Hefti, 1990) and cortical neurons (Rosenberg, 1988). It has been suggested that dopamine may also play a role in retinal degeneration in the rd mouse, because antagonists for D1R or D2R, as well as dopamine depletion blocked photoreceptor cell death in rd mouse retinas maintained in organotypic cultures (Ogilvie and Speck, 2002). In contrast, we showed that dopamine has an antiapoptotic effect in early postnatal retinas (Fig. 4), mediated by an atypical D1-like receptor coupled to stimulation of adenylyl cyclase, followed by activation of cyclic AMP-dependent protein kinase (Varella et al., 1999). Other authors demonstrated that either dopamine or a D1-agonist inhibited glutamate-induced activation of nitric oxide synthase, thus resulting in protection of retinal neurons (Yamauchi et al., 2003). Several studies indicated that dopamine induced cell death may be related to its oxidation status. For example, dopamine toxicity in striatal cultures was

Fig. 4. Neuroprotection by activated dopaminergic receptors, through cAMP-dependent protein kinase. The histogram shows the rate of cell death in the NBL of retinal explants from neonatal rats, following 24 h incubation with various combinations of control medium (CTR), 10 mM forskolion (FORSK), 100 mm of the D1 dopamine receptor agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (6-Cl-PB), or 20 mM of the PKA inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89). Data from Varella et al. (1999).

inhibited by the addition of ascorbic acid (Cheng et al., 1996). Such data were taken as evidence that the degeneration of dopaminergic neurons in Parkinson’s disease can be caused by an imbalance between dopamine oxidation and anti-oxidant responses (Hastings et al., 1996). In contrast, the protective effect of dopamine in the retina is similar to the protection conferred by ascorbic acid (M.H. Varella and R. Linden, unpublished data). 4.5. Adrenergics Adrenergic neurotransmitters and their receptors, as well as evidence for adrenergic signaling in both developing and adult mammalian retina, were reported in several studies (Hadjiconstantinou et al., 1984; Bylund and Chacko, 1999; Ferrari-Dileo, 1988; Venkataraman et al., 1996; Shelke et al., 1997; Wheeler and WoldeMussie, 2001; Lograno et al., 2000; Cutcliffe and Osborne, 1987; Zarbin et al., 1986). Certain studies indicated that adrenergic mechanisms may be involved in retinal ganglion cell death, and b-adrenergic receptor blockers such as betaxolol or timolol have been widely used as neuroprotective agents in glaucoma models (see Osborne et al., 2004, for review). However, many of these studies were performed in vivo with either systemic or topical drug application (Osborne et al., 1999; Wood et al., 2001), providing indirect effects through non-retinal cells, such as retinal arteries (Hoste and Sys, 1994). Recently, direct effects of adrenergic modulators were examined in cultured retinal cells. It was reported that the b1-adrenergic receptor antagonist betaxolol and the a-2 agonist UK14,304 protected cultured rat retinal cells against glutamate-induced cell death (Baptiste et al., 2002). These pharmacological agents also blocked the NMDA-induced increase in intracellular calcium concentration in isolated rabbit ganglion cells. It was reported that betaxolol-induced protection is mediated by the blockade of ion channels, similar to previous studies (Melena et al., 1999; Chidlow et al., 2000). In contrast, the protective effect of UK14,304 depended on the specific activation of the a-2 adrenergic receptor. Some studies demonstrated an anti-apoptotic function of a-2 adrenergic receptor agonists against induced ischemia (Vidal-Sanz et al., 2001; Lai et al., 2002), suggesting that a-2 adrenergic receptors activate neuroprotective signaling pathways that block glutamateinduced calcium increase and neuronal cell death. In fact, one study reported the specific regulation of antiapoptotic molecules such as Bcl-2 and Bcl-xL, but not Bax, and activation of anti-apoptotic signaling pathways, as a possible explanation of the protective effect of the a-2 adrenergic agonist brimonidine against ischemiainduced cell death (Lai et al., 2002). Other studies indicated that the protective actions of adrenergic

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receptor modulators were associated to the synthesis of neurotrophic factors, such as bFGF, BDNF or CNTF (Wen et al., 1996; Chao et al., 2000; Wood et al., 2001; Agarwal et al., 2002; Lai et al., 2002). Altogether, these studies suggest a neuroprotective role for adrenergic receptors in adult mammalian retina, but no data are as yet available during retinal development. 4.6. Serotonin Serotonin protects serum-deprived developing cardiomyocytes in vitro, through the activation of 5-HT2b receptors. In addition, morphological and biochemical evidence of mitochondrial dysfunction was found in 5-HT2b knock-out mice, although without accompanying increase in cell death in their hearts (Nebigil et al., 2003). Protective effects of serotonin were also observed in neuronal cells. Serotonin prevented cell death among cultured embryonic cortical cells, through 5-HT2a receptors (Dooley et al., 1997), while neuroprotective effects of serotonin through 5-HT1a receptors have also been described in cortical, hippocampal neurons both in vitro and in vivo (see Azmitia, 2001, for review). Serotonin receptors are expressed in the mammalian retina. The expression of 5-HT1b was detected by in situ hybridization in both developing and adult mouse retina (Upton et al., 1999). Transcripts for both 5-HT1a and 5-HT7 were found in adult rat retina (Pootanakit and Brunken, 2000). In adult rabbit retina, expression of mRNA for 5-HT1a, 5-HT2a, 5-HT3a, 5-HT3b and 5-HT7 was detected and immunohistochemical assays demonstrated protein expression of 5-HT2a and 5-HT3 subunits (Pootanakit et al., 1999; Pootanakit and Brunken, 2001). Modulation by serotonin of intracellular levels of both cAMP and IP3 was previously taken as evidence for functional signaling of serotonin receptors in retinal tissue (Cutcliffe and Osborne, 1987; Blazynski et al., 1985). A handful of studies investigated effects of serotonin upon cell death in the developing mammalian retina. Various 5-HT2 receptor antagonists partially protected cultured ganglion cells isolated from the retina of postnatal rats against glutamate-induced cell death. Furthermore, it was demonstrated that in vivo inactivation of 5-HT2 receptors prevented a decrease in retinal tissue thickness following ischemia-reperfusion (InoueMatsuhisa et al., 2003). The authors interpreted these data as a pro-apoptotic effect of serotonin upon rat retinal ganglion cells, mediated by 5-HT2 receptors. However, cell death was inferred by quantification of neurite size, which is not compelling. Toxic effects of serotonin through 5-HT2 receptors had been previously suggested from studies of 3,4-methylenedioxy-methamphetamine (MDMA; ecstasy)-induced toxicity in vitro and in vivo (Azmitia et al., 1990; Schmidt et al., 1990).

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In contrast with the results reported for the retina, an anti-apoptotic effect of serotonin was suggested for the cerebral cortex (Dooley et al., 1997). Further investigation is, therefore, needed to assess the physiological role of serotonin upon cell death during retinal development. 4.7. Acetylcholine In addition to the above-mentioned early evidence for cell death induced by blockade of cholinergic receptors in developing autonomic ganglia, it has been reported that activation of nicotinic receptors protects both cortical cells and ciliary ganglion cells against induced apoptosis (Hejmadi et al., 2003; Pugh and Margiotta, 2000). Recently, however, a decrease in the frequency of TUNEL-positive cells in the olfactory bulb was found in adult knock-out mice for the b2 subunit of the nicotinic receptor (Mechawar et al., 2004), suggesting a proapoptotic role for nicotinic signaling upon olfactory bulb cells. Functional nicotinic and muscarinic cholinergic receptors have been described in embryonic, postnatal and adult mammalian retinas (Cutcliffe and Osborne, 1987; Wong, 1995b; Hruska et al., 1978; Neal and Dawson, 1985; Hutchins, 1987; Feller, 2002; Moretti et al., 2004). Activation of M1 muscarinic receptors maintains the survival of developing ganglion cells in vitro (Pereira et al., 2001), and the same effect was recently observed in adult retinal ganglion cells (Wehrwein et al., 2004). In addition, it was reported that acetylcholine, through the activation of nicotinic receptors, protects cultured retinal cells against excitotoxic cell death. In the latter case, it was proposed that effect of acetylcholine depends on the release of dopamine (Yasuyoshi et al., 2002). Thus, cholinergic receptor activation has a protective role in the developing retina. Nicotinic activation of the Erk signaling pathways was demonstrated in other neuronal cell types (Dajas-Bailador et al., 2002), but the intracellular signaling mechanisms mediating cholinergic neuroprotection in the retina are still unknown. In summary, although cholinergic receptor activation has a protective role in the developing retina, it is still unclear whether that is the case in the control of naturally occurring cell death during retinal development. 4.8. Purines 4.8.1. Adenosine Adenosine has been reported both as a neuroprotective neurotransmitter (Logan and Sweeney, 1997; Vitolo et al., 1998; Alfinito et al., 2003; Matsuoka et al., 1999; Michel et al., 1999), as well as a pro-apoptotic factor (Barth et al., 1997; Cassada et al., 2001) in various regions of the nervous system.

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Expression of functional adenosine receptors in adult mammalian retina has been demonstrated by various methods (reviewed in Blazynski and Perez, 1991). Adenosine-mediated neuroprotection was reported in a model of ischemic preconditioning in adult mammalian retina (reviewed in Roth, 2004), suggesting a role for this neurotransmitter in this pathological condition. Interestingly, it has been suggested that the activation of adenosine receptors can lead to Trk receptor activation (Lee and Chao, 2001; Rajagopal et al., 2004), which may help explain the neuroprotective effect of the purine. Both A1 and A2 adenosine receptors are present since early stages of chick retina development (Paes-deCarvalho, 2002). The only data reported for immature mammalian retina are the expression of A2a receptors in ganglion cells and in the INL during retinal development in dogs (Taomoto et al., 2000). However, regulation of cell death by adenosine has been demonstrated in developing chick retina. Chronic activation of A2a adenosine receptors protected chick retinal neurons against either glutamate- or medium change-induced cell death. Interestingly, treatment with adenosine deaminase lead to an increase in cell death in retinal cultures, suggesting that endogenous adenosine regulates cell survival of chick retinal neurons (Ferreira and Paes-deCarvalho, 2001; Paes-de-Carvalho et al., 2003). It is still an open question whether this neurotransmitter plays a role in the control of cell survival during mammalian retinal development. 4.8.2. ATP Expression of purinergic receptors in mammalian retina is extensively documented. Expression of mRNA for P2X2, P2X3, P2X4, P2X5 and P2X7 subunits of ATP receptors was detected in adult rat retina (Brandle et al., 1998; Jabs et al., 2000; Wheeler-Schilling et al., 2000; Wheeler-Schilling et al., 2001). P2X receptors protein was confirmed in the retinas of adult rats, monkeys and humans (Puthussery and Fletcher, 2004; Ishii et al., 2003; Pannicke et al., 2000). The expression of the metabotropic purinergic receptor P2Y was also demonstrated in Mu¨ller cells of the retina of both adult humans and rabbits (Bringmann et al., 2002; Meyer et al., 2002). In contrast, few studies reported purinergic receptors during retinal development. An increase in intracellular calcium was found after activation of purinergic receptors by ATP during embryonic development of chick retina (Sugioka et al., 1996), and treatment of cultured ganglion cells from developing rat retina with exogenous ATP, induced P2X receptormediated currents and Ca+2 influx in a subpopulation of RGCs, but not amacrine cells (Taschenberger et al., 1999). Similar to data reported for activation of adenosine receptors, activation of other purinergic receptors was reported to induce either cell death or neuroprotection

in both the CNS and PNS. Pharmacological inactivation of P2 receptors protected CNS neurons against induced cell death, suggesting a pro-apoptotic role for purinergic signaling (Volonte and Merlo, 1996, Volonte et al., 1999). Conversely, activation of these receptors by ADP protected cerebellar granule cells (Vitolo et al., 1998). These data support the idea that activation of P2X receptors can activate either pro- or anti-apoptotic signaling pathways. Evidence for an indirect neuroprotective action of purinergic receptors has also been obtained, where the activation of microglial P2X7 receptors led to TNF production and TNF-dependent neuronal protection against glutamate-induced cell death (Suzuki et al., 2004). Data regarding control of retinal cell death by purinergic receptors are, however, not available. In summary, the available data indicate that various neurotransmitters regulate cell death in the developing CNS. Evidence was gathered for contrasting effects upon neuronal death, that is, glutamate, purines, serotonin and dopamine may either induce or block neuronal death in distinct areas of the CNS. In the mammalian retina, compelling evidence was shown for both toxic and protective effects of glutamate. Although glutamatergic receptor activation has been suggested as the molecular basis of some pathological situations of the adult retina, it is unclear whether glutamate may have such a role during development. Conversely, it was clearly demonstrated that glutamate, dopamine and adenosine are neuroprotective for immature retinal cells. It is noteworthy, however, that current evidence is not enough to define a role for these transmitters as physiological regulators of PCD in the developing mammalian retina. In addition, other neurotransmitter systems are present and active within the developing retina. Further investigations will be necessary to examine whether these molecules also affect cell death during mammalian retinal development.

5. Neuropeptides Neuropeptides are evolutionarily ancient extracellular messengers, which were described in organisms as simple as hydra (Sherwood et al., 2000; Ho¨kfelt et al., 2000). It is usually assumed that neuropeptides function as neuromodulators, and differ from classical neurotransmitters in several features. One important aspect is that neuropeptides are found in tissues at concentrations in the nanomolar to micromolar range, while classical neurotransmitters are found in the millimolar range. The affinities of their respective receptors are consistent with tissue concentrations, because neuropeptides activate their receptors in much lower concentrations than neurotransmitters.

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Other differences include the mechanisms of biosynthesis, storage and secretion. Neuropeptides are first produced as large precursors that may be cleaved and modified to generate one or more active peptides. Part of this process occurs in the large dense core secretory vesicles (LDCV) where they are stored. The release of neuropeptides is still a matter of debate, but it is believed that, whereas classical neurotransmitters are released and give rise to post-synaptic currents within milliseconds, responses to neuropeptides are about 100-fold slower. This difference may be partly accounted for by post-synaptic events, but slow release is considered an important element. It has been suggested that a key factor is the intracellular location of LDCV relative to Ca2+ channels. Recently, a study of the kinetics of neuropeptide secretion demonstrated that cargo release is considerably slower than expected and that complete fusion of LDCV is necessary for peptidergic neurotransmission (Barg et al., 2002). Most neuropeptide receptors belong to the GPCR superfamily, and evidence accumulates on the various signaling pathways that may be activated by these receptors. It is also interesting that many neuropeptides exert their effects through the activation of different subtypes of receptors, amplifying the range of possibilities of interference in cellular physiology (Darlison and Richter, 1999, for review). 5.1. Retinal neuropeptide systems During the last 30 years the investigation of the expression and function of peptidergic systems in the nervous system has increased, but compelling data on their roles are still scarce. The selection of peptide families discussed here is based on their presence in retinal tissue and on evidence for their roles as modulators of cell death within the nervous system. Their expression, as well as that of their receptors in the retina and known functional properties will be reviewed first, followed by a general discussion of their role in the control of sensitivity to cell death. A more detailed description of retinal peptides may be found in a recent review (Bagnoli et al., 2003). 5.1.1. Substance P and other tachykinins Substance P (SP) is a member of the tachykinin family of peptides that also includes neurokinin A, neurokinin A-related peptides and neurokinin B. The physiological actions of these peptides are mediated by the lowaffinity GPCRs NK1, NK2 and NK3, which are preferentially activated by SP, neurokinin A and neurokinin B, respectively (Ho¨kfelt et al., 2001). A generalized pattern of expression of retinal tachykinins is known from studies employing antibodies that did not discriminate between SP and other tachykinins. The results indicated that these peptides are expressed

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early in the development of mammalian retinal tissue (Nguyen-Legros et al., 1986; Zhang and Yeh, 1992; Jotwani et al., 1994; Casini et al., 1997a, b; Bagnoli et al., 2003, for review). Tachykinin mRNA and immunoreactivity have been located in amacrine cells and displaced amacrine cells, and in ganglion cells of some species (Casini et al., 1997a, b). NK1 and NK3 receptors were also detected in the mammalian retina, but NK2 was not. NK1 was shown at early postnatal ages whereas NK3 was detected only by the time of eye opening, suggesting distinct roles for SP and neurokinin B (Oyamada et al., 1999). Distinct distributions were found between the retinas of rat and rabbit. In the rat, NK1 is expressed in GABAergic interplexiform and amacrine cells, as well as in most dopaminergic amacrine cells, whereas in the rabbit, besides in dopaminergic amacrine cells, it was also found expressed by a population of cone bipolar cells (Casini et al., 1997a, b, 2002). Recently, data on the expression of NK1 receptor in the mouse retina seem to confirm the pattern observed in rat and rabbit retinas, with respect to expression in dopaminergic amacrine cells. Moreover, it was suggested the putative expression of these receptors also in SP-containing amacrine cells in the mouse (Catalani et al., 2004). Little is known of the roles of SP in developing and mature mammalian retinas, but it was suggested that this peptide has an excitatory effect on ganglion cells (Dick and Miller, 1981; Zalutsky and Miller, 1990). Expression of NK1 receptors in dopaminergic amacrine cells may indicate a role in the modulation of dopaminergic communication (Casini et al., 1997a, b, 2002; Catalani et al., 2004). 5.1.2. Somatostatin Somatostatin (or SRIF, for somatotropin release inhibitory factor) is a neuroactive peptide that may occur in two forms: SRIF-14 and SRIF-28. In the retina, either form may prevail during development and among mammalian species. There are also differences in the cell populations expressing this peptide and in the pattern of expression during development (Bagnoli et al., 2003, for review). In general, the SRIF-positive cells are located in the innermost region of the INL and in the ganglion cell layer (GCL) (Cristiani et al., 2002). In rat retina, SRIF IR cells were described already at embryonic day 16, in neuroblasts that reach the GCL at embryonic day 20 (Ferriero and Sagar, 1987). This peptidergic system was described in both adult and developing retinas of various mammalian species, such as rat (Ferriero and Sagar, 1987; Ferriero et al., 1990), cat (White and Chalupa, 1992) and human (Mitrofanis et al., 1989). Interestingly, in the rat and cat retinae, SRIF was detected transiently in ganglion cells (Xiang et al., 2001; Mitrofanis et al., 1989; White and Chalupa, 1992).

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Five receptors were described that respond to SRIF, sst1 to sst5, which differ in functional and pharmacological properties (Csaba and Dournaud, 2001). In the mouse retina, a detailed characterization was made of receptor expression in various cell populations (Cristiani et al., 2002). RT-PCR detected mRNA for all five sst receptors, with the highest levels of sst2 and sst4. SRIF immunolabeling was located in sparsely distributed amacrine cells in the INL, as well as in displaced amacrine cells in the GCL. Sst2A receptors were identified in protein kinase (PKC)–IR rod bipolar cells, TH-IR amacrine cells, calbindin (CaBP)-IR horizontal cells and glycinergic amacrine cells. None of the sst2A-IR amacrine cells were found to express parvalbumin (PV) immunoreactivity. Immunolabeling for the sst4 receptor was detected in both CaBP-IR and CaBP-non-IR cells in the GCL that were identified as ganglion cells (Cristiani et al., 2002). The detailed characterization of SRIF and sst receptors strongly suggests that SRIF may be an important regulator of synaptic communication in the mammalian retina (discussed in Cristiani et al., 2002). Among other roles, it has been recently shown that the sst1 receptor may function as an autoreceptor, negatively regulating SRIF release in rat retina (Mastrodimou and Thermos, 2004), and that in rod bipolar cells, which express sst2A receptors, SRIF may inhibit a K+ depolarization-induced [Ca2+]i response (Johnson et al., 2001). 5.1.3. Neuropeptide Y Neuropeptide Y (NPY) belongs to a family that includes peptide YY and pancreatic polypeptide. Five NPY receptors were identified, Y1, Y2, Y4, Y5, Y6, and the function of a Y3 receptor remains to be determined, as it is the only receptor that has not yet been cloned (Michel et al., 1998). These receptors belong to the Gprotein receptor superfamily. Their activation leads to inhibition of adenylyl cyclase, and blockade of Ca2+ channels may also occur (Michel et al., 1998). In mammalian retinas, immunoreactivity for NPY was detected in amacrine and displaced amacrine cells. In some species, such as cat and human, NPY was also found in ganglion cells (Oh et al., 2002). Moreover, in the retina of the rat, NPY-positive cells appear in the GCL at late prenatal stages, and a transient increase in the expression of this peptide was found close to the time of eye opening (Ferriero and Sagar, 1989). NPY is suggested to be a potent inhibitory neuropeptide, and strongly affects rod bipolar cells, through negative regulation of Ca2+ influx and consequent inhibition of glutamate release (D’Angelo and Brecha, 2004). 5.1.4. Corticotrophin releasing factor and related peptides Corticotrophin releasing factor (CRF or CRH, for corticotrophin releasing hormone) is a peptide of 41

amino acids, and belongs to a family that includes urocortin, sauvagine and urotensin. It was isolated for its ability to induce the secretion of pro-opiomelanocortin-derived peptides, such as adrenocorticotropic hormone (ACTH), from the anterior pituitary gland (Vale et al., 1981). CRF activates two GPCRs, CRFR1 and CRFR2, that are biochemically and pharmacologically distinct. Both receptors stimulate adenylyl cyclase (De Souza, 1995; Perrin and Vale, 1999). CRF is located in amacrine and displaced amacrine cells (Marshak, 1989; Yeh and Olschowka, 1989). Immunoreactivity is detected in rat retinas at 3 days after birth, in cells on the NBL as well as in the GCL (Zhang et al., 1990). However, similar to other retinal peptides, there are changes in CRF during the development, and a peak of expression is observed close to the period of eye opening (Zhang et al., 1990). 5.1.5. Angiotensin Angiotensin is well known for its role in cardiovascular regulation, neuroendocrine functions and control of fluid balance. However, increasing evidence is available that this peptide may modulate both cell growth and cell survival in several tissues (reviewed in Lucius et al., 1999). The expression of angiotensin during development of the retinal tissue remains elusive. However, Kohler et al. (1997) measured in the rabbit retina the content of angiotensin II by radioimmunoassay, and provided evidence of synthesis of angiotensin II by the detection of mRNA for angiotensin-converting enzyme (ACE). Immunoreactivity for angiotensin was found in amacrine cells in the inner border of the INL, in fibers of both the inner and outer plexiform layers, and in Mu¨ller cells and their processes. Ganglion cell labeling was not conclusive. Angiotensinogen mRNA was also described in the rat retina (Murata et al., 1997a). Altogether, these data indicate local synthesis of angiotensin II. Investigation of angiotensin II receptors by RT-PCR demonstrated that AT1A and AT2, but not AT1B, were expressed at least from postnatal day 3 onwards in the rat retina (WheelerSchilling et al., 1999; Murata et al., 1997b). Immunohistochemistry in adult retinas showed immunolabel for AT1 (irrespective of the subtype) in ganglion cells and also in some cells in the INL. In situ hybridization in postnatal day 14 rats showed labeling of mRNA for the AT2 in the GCL (Wheeler-Schilling et al., 1999). The role of the renin-angiotensin system (RAS) in the visual system was investigated by testing the effects of the ACE inhibitor captopril on eletroretinogram and other functional aspects, and it was suggested that RAS may be involved in retinal neurotransmission, in addition to its vascular effects (Jurklies et al., 1995). It was also shown that angiotensin II can interfere on calcium currents in ganglion cells of the rat retina (Guenther et al., 1996).

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5.1.6. Opioid peptides Opioid peptides constitute a family of endogenous ligands which may activate distinct GPCRs. For example, b-endorphin activates e-opioid receptors, dinorphin A1–17 activates k-opioid receptors, endomorphin 1 and 2 activate m-opioid receptors and enkephalins activate d-opioid receptors (Janecka et al., 2004; Nock et al., 1993). An additional opioid with multiple actions as a growth factor is [Met5]-enkephalin or opioid growth factor (OGF), and its actions are suggested to be mediated by a distinct receptor (Zagon et al., 2002). Several opioid peptides were detected in the mammalian retina. Early studies detected the expression of m-opioid receptors in ganglion cells of rats and monkeys, and of enkephalins in guinea pig and developing human retinas (Wamsley et al., 1981; Altschuler et al., 1982; Yew et al., 1991; Jotwani et al., 1994). Moreover, [Met5]enkephalin, preproenkephalin mRNA and [Met5]-enkephalin binding sites were detected in the NBL and in the GCL of early postnatal as well as prenatal rat retinas (Isayama et al., 1991, 1995), and preproenkephalin mRNA was found in the INL of adult rat retinas (Isayama et al., 1996). Limited evidence suggests that [Met5]-enkephalin can modulate cell proliferation in retinal tissue (Isayama et al., 1991). 5.1.7. Pituitary adenylyl cyclase-activating polypeptide and vasoactive intestinal peptide Pituitary adenylyl cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) belong to the secretin/glucagon superfamily. PACAP was first isolated for its ability to induce the production of cAMP in the anterior pituitary of rats (Miyata et al., 1989). The PACAP precursor molecule is post-translationally processed into two biologically active products, PACAP38 and PACAP27 (Miyata et al., 1989, 1990), which share high amino acid homology with VIP. Both PACAP and VIP act on common receptors. Molecular cloning revealed three distinct receptors: PAC1, VPAC1 and VPAC2, of which the PAC1 receptor is selective for PACAP (Harmar et al., 1998; Vaudry et al., 2000, for review). VIP is present in the INL, inner plexiform layer and GCL in rabbit retinas (Casini and Brecha, 1991). In adult rats, mRNA for this peptide was identified by in situ hybridization in amacrine cells located in the INL, and in a very small number of displaced amacrine cells. VIP was identified as soon as 5 days after birth in the inner stratum of the NBL (Casini et al., 1994). The description of PACAP expression is restricted to adult rat retinas in the ganglion cell, inner plexiform and INLs (Seki et al., 1998), and to fetal human retinas at 12–18 weeks of gestation (Olianas et al., 1997). On the other hand, expression of PACAP receptors was observed in ganglion and amacrine cells, inner

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plexiform layer, outer nuclear layer and outer plexiform layer in adult rat retinas (Seki et al., 1997, 1998), as well as in all layers in early postnatal rat retina (Silveira et al., 2002). The regulation of circadian rhythms is an important function attributed to PACAP and VIP produced by ganglion cells (Hannibal, 2002; Hannibal and Fahrenkrug, 2003, 2004). 5.2. Control of programmed cell death by neuropeptides In general, little attention has been paid to the role of neuropeptides as regulators of the sensitivity to PCD. Evidence for such a role in retinal tissue is particularly scarce, but several neuroactive peptides were shown to affect cell survival within the nervous system. Both a protective (Lallemend et al., 2003) as well as a pro-apoptotic effect of SP (Zachrisson et al., 1998; Liu et al., 1999) have been reported in the nervous system. Recently, Lallemend and collaborators (2003) showed that SP protects spiral ganglion neurons from cell death induced by trophic deprivation. This effect was dependent on the activation of Gq-coupled NK1 receptors, and on an increase in intracellular calcium, was partially reverted by PKC inhibitors and was completely blocked by a MEKI inhibitor. Interestingly, NK1 receptor localization seemed to be intracellular, suggesting that the receptor is internalized (Lallemend et al., 2003). Further investigation will be necessary to evaluate the value of this observation, but another study indicated that proliferative and anti-apoptotic effects of SP are facilitated by formation of a b-arrestin-dependent scaffolding complex (DeFea et al., 2000). In contrast, it has also been shown that SP can induce cell death, possibly dependent on its ability to modulate glutamate excitotoxicity. Liu et al. (1999) reported that mice bearing a disruption of the preprotachykinin gene, and therefore express neither SP nor neurokinin A, are resistant to kainate excitoxicity. Both necrosis and apoptosis of hippocampal neurons were prevented, and neither caspase-3 nor Bax, that are induced by kainate in wild-type mice, were altered in mutant mice (Liu et al., 1999). It had also been shown that pretreatment with NK1 antagonist CP-122,721-1 before administration of kainate decreased seizure activity and counteracted KA-induced nerve cell death in CA1 (Zachrisson et al., 1998). Another intriguing result showed that SP induces a non-apoptotic, non-necrotic form of cell death in hippocampal, striatal and cortical neuronal cultures in 48 h in micromolar concentrations, and in 7 days in nanomolar concentrations (CastroObrego´n et al., 2002). In this case, it was proposed that the effect was independent of glutamate effects (CastroObrego´n et al., 2002). Nonetheless, despite the evidence for both pro- and anti-degenerative effects in the nervous system, no

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evidence is as yet available on a role of SP and other tachykinins upon the sensitivity to cell death in the retina. A toxic effect of SRIF upon the cerebellum was described, and reportedly counteracted by diazepam (Balaban et al., 1988). In contrast, SRIF protected cortical cells from NMDA-induced cell death through cGMP-dependent protein kinase (Forloni et al., 1997). Activation of the Y1, Y2 and Y5 receptors for NPY protected hippocampal cells against excitotoxic neurodegeneration in organotypic cultures (Silva et al., 2003). The mechanism of neuroprotection is not known, but a candidate mechanism could be the inhibition of Ca2+ influx and glutamate release (McCullough et al., 1998; Silva et al., 2001; Klapstein and Colmers, 1997). Again, no data are available on neuroprotection or other effects of either SRIF or NPY upon retinal cell death. It has been shown that selective activation of d-opioid receptors may protect neocortical neurons from glutamate-induced excitotoxic injury, an effect that is not shared by m- or k-opioid receptor activation (Zhang et al., 2000a, b). Treatment with d-opioid peptides also enhanced the survival of rat dopaminergic cells both in vitro and in vivo (Borlongan et al., 2000). In turn, activation of m-opioid receptors enhanced the survival of both SH-SY5Y cells and cortical neurons under trophic factor deprivation, dependent on a signal transduction pathway involving Gi/o and PI3 kinase (Iglesias et al., 2003). Moreover, low concentrations (femto- to nanomolar) of [D-Ala2, D-Leu5]enkephalin (DADLE) promoted cell survival of serum-starved PC12 cells via d2-opioid receptors and activation of the MEK-Erk pathway, whereas high (micromolar) concentrations of the same peptide promoted cell death mediated by an increase of FasL through an as yet unknown mechanism involvingm-opioid receptors (Hayashi et al., 2002). It has also been suggested that the cellular and molecular mechanisms of opioid tolerance may include apoptotic cell death, as a neurotoxic response to prolonged opioid administration. This cell death in spinal neurons was attributed to deregulated glutamate neurotransmission, leading to upregulation of Bax and caspase-3 and downregulation of Bcl-2 (Mao et al., 2002). The major role for corticotrophin release factor (CRF) is the regulation of the hypothalamic-pituitaryadrenal axis. However, recent data point to an additional cytoprotective role of the CRF family. For example, CRF supressed apoptotic cell death in Y79 retinoblastoma cells treated with the DNA-damaging agent camptothecin, and the protective effect was dependent on PKA activity (Radulovic et al., 2003). Lezoualc’h et al. (2000) showed that CRF protected hippocampal neurons against oxidative insults. This effect was blocked by PKA inhibitors and was accompanied by the suppression of the activity of the transcription factor NFkB. Other groups confirmed this

neuroprotective effect of CRF, as well as of urocortin against excitotoxicity in hippocampal slice cultures, dependent upon cAMP and MAPK, and with a concomitant inhibition of JNK/SAPK phosphorylation (Elliott-Hunt et al., 2002). Urocortin also had a potent cytoprotective activity against cell death induced by amyloid b-peptide, oxidative stress, a product of lipid oxidation and the excitatory neurotransmitter glutamate (Pedersen et al., 2002). The mechanism proposed required again activation of PKA, as well as protein kinase C and MAP kinase (Pedersen et al., 2002, 2001). Interestingly, in addition to Gsa, CRF receptors are coupled to other G proteins, including Gq/11, linked to phospholipase C activation, IP3 production and PKC activation (Grammatopoulos et al., 2000, 2001), which may also be involved in the neuroprotective effect. In addition to hippocampal and cortical cultures, CRF peptides also prevented apoptotic cell death of cerebellar granule neurons triggered by inhibition of PI3 kinase (Facci et al., 2003). Treatment with PI3 K inhibitors reduced neuronal activation of Akt/PKB, while increasing the ratio of non-phosphorylated to phosphorylated GSK3. CRF peptides, in turn, promoted GSK3 phosphorylation without PKB activation, suggesting that the cellular mechanism for neuroprotection in cerebellar neurons depends on phosphorylation of GSK3 by PKA. On the other hand, CRF and forskolin produced additive effects on the reduction of Ab142 neurotoxicity in hippocampal and cortical neurons, suggesting parallel pathways. Moreover, Rp-8-BrcAMPS, as well as U0126 failed to inhibit CRF neuroprotection against Ab142 (Facci et al., 2003). The mechanism of CRF neuroprotection in this paradigm remains to be uncovered. In contrast with considerable evidence for neuroprotection by CRF peptides, it was shown that CRF induced apoptosis in PC12 cells, in which activation of the CRF1 receptor led to production of Fas ligand mediated by activation of p38 kinase (Dermitzaki et al., 2002). Studies in vivo indicated that CRF antagonists can prevent degeneration induced by ischemic, excitotoxic and traumatic insults (Lyons et al., 1991; Strijbos et al., 1994; Roe et al., 1998). However, recent work suggested CRF is not directly toxic to neurons in vitro or in vivo, nor increases cell death induced by excitatory amino acids (Craighead et al., 2000). One possible explanation for these apparently contradictory results is that CRF peptides may protect neurons from apoptosis induced by acute injury, while promoting necrosis under conditions of chronic injury. Additional effort will be necessary to test this hypothesis. Recent studies suggest effects of angiotensin in the modulation of neuronal survival. Both induction of cell death as well as protective effects were described. Angiotensin protected cortical neurons exposed to chemical-induced hypoxia, through activation of the

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AT2 receptor (Grammatopoulos et al., 2002), and this was related to inhibition of caspase-3 cleavage (Grammatopoulos et al., 2004). This peptide also protected from NMDA excitotoxicity both primary cultures from the hypothalamus/thalamus/septum/midbrain (HTSM) region of 1-day-old mice (Jing et al., 2004), as well as neuronal cell lines (Schelman et al., 2004). Schelman et al. (2004) suggested that this effect depends on both AT1 and AT2 receptors, and is related to the modulation of Bcl-2 expression. In contrast, in PC12W cells activation of the AT2 receptor induced cell death through dephosphorylation of MAP kinase (Yamada et al., 1996). It had been previously shown that MAP kinase phosphatase 1 was activated by engagement of the AT2 receptor and, in fact, treatment with vanadate as well as antisense oligonucleotides to that phosphatase blocked AT2 receptor-mediated apoptosis. This demonstrated that the activation of MAPK phosphatase 1 is essential for induction of apoptotic cell death (Yamada et al., 1996). In addition, in the same experimental model, angiotensin reverted the protective effect of acetylcholine, which involved activation of JAK2 (Shaw et al., 2003). Here again, the effect of angiotensin depended on the AT2 receptor, and on activation of the SHP1 phosphatase that antagonizes JAK2 (Shaw et al., 2003). Similar data were obtained in insulin-treated PC12 cells, in which angiotensin inhibited Akt activation through SHP1, thereby inducing apoptosis (Cui et al., 2002). Despite the presence of AT receptors in the retina, effects of angiotensin upon retinal tissue remain to be tested. Among the secretin/glucagon neuropeptide family, early evidence was reported for multiple effects of VIP upon sympathetic neuron precursors in culture, including stimulation of mitosis, neurite outgrowth and survival (Pincus et al., 1990). PACAP also had a neuroprotective effect on DRG neurons (Lioudyno et al., 1998). It was also found that low concentrations of VIP, as well as of activity-dependent neurotrophic factor (ADNF)-9 or NAP (peptide derivatives of a product secreted by glial cells in response to VIP), protected PC12 cells, SH-SY5Y neuroblastoma cells and rat cerebellar granule cells against the toxicity of dopamine and 6-hydroxydopamine, but not against MPP+ ion (Offen et al., 2000). PACAP was also neuroprotective and counteracted behavioral deficits in an experimental rat model of Parkinson’s disease (Reglo´di et al., 2004). The investigation of the role of PACAP in olfactory neurons survival also support the importance of this peptide in olfactory neurogenesis (Hansel et al., 2001). Protection of cortical neurons by PACAP upon NMDA treatment was dependent on the reestablishment of BDNF synthesis (Frechilla et al., 2001). Another study assessed the protective role of VIP against excitotoxic lesions induced by the glutamatergic analog ibotenate in developing mouse brain. VIP co-

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treatment reduced ibotenate-induced cortical lesions. VIP protective effects were reproduced by a peptide derived from ADNF, a trophic factor released by VIPstimulated astrocytes, and by stearyl norleucine VIP, a specific VIP agonist that does not activate adenylate cyclase. Moreover, neither forskolin nor PACAP provided VIP-like protection (Gressens et al., 1997). These data suggest the existence of a VIP specific receptor or of a intracellular pathway specifically activated by VIP, but direct evidence to support these hypotheses is lacking. In cerebellar neurons, PACAP-induced protection against hydrogen peroxide-, ethanol- or ceramideinduced cell death was dependent on MAP kinase (Vaudry et al., 2002a, b, 2003). In the latter case, the neuroprotective effect was mimicked by either db-cAMP or forskolin, and prevented by the MEK inhibitor U0126. Moreover, PACAP reduced the amount of activated JNK. However, the effect was not blocked by H89 or chelerythrine, which indicated that it was independent of PKA and PKC (Vaudry et al., 2003). In contrast, PACAP-induced protection of cerebellar neurons cultured in low potassium concentrations was dependent both on cAMP/PKA and PI3 kinase pathways and, unexpectedly, ethanol exposure potentiated the anti-apoptotic effect of PACAP (Bhave and Hoffman, 2004). Recently, it was shown that the protective effect of PACAP upon cerebellar cells may involve its ability to inhibit delayed rectified K+ currents (Mei et al., 2004). Other studies suggest that protection of hippocampal neurons by PACAP involves inhibition of both JNK/SAPK and p38 pathways by both PACAP itself and by IL-6 secreted in response to the peptide (Shioda et al., 1998). Despite the abundant evidence for the expression of various neuroactive peptides and their receptors in the mammalian retina, the only studies of the control of retinal cell death by neuropeptides were done with PACAP and VIP. Early studies showed that VIP prevents TTX-induced retinal ganglion cell death in vitro, through an increase of cAMP levels (Kaiser and Lipton, 1990). Subsequently, it was shown that PACAP prevented excitotoxic cell death of cultured retinal neurons from neonatal Wistar rats. Simultaneous application of PACAPs 10 nM–1 mM and glutamate 1 mM for 10 min inhibited the delayed death of retinal neurons at 24 h after treatment with the excitatory amino acid. Protection by PACAP was antagonized by the PKA inhibitor H-89, and PACAP increased cAMP levels in a dose-dependent manner. In addition, activation of MAP kinase by PACAP38 was prevented by simultaneous application of H-89. These findings suggested that PACAP attenuates glutamate-induced delayed neurotoxicity in cultured retinal neurons, through MAP kinase activated by PKA (Shoge et al., 1999).

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2000; Pedersen et al., 2001, 2002) and cerebellum (Facci et al., 2003). This highlights the central role of intracellular pathways activated by cAMP upon the control of neuronal cell death (discussed in Silveira and Linden, 2004). Recently, Lee et al. (2002) suggested an alternative possibility that the activation of PACAP receptors can trigger Trk receptor activation, and the same group presented evidence for Trk receptor activation in intracellular membranes (Rajagopal et al., 2004). However, preliminary experiments using the tyrosine kinase inhibitor k252a suggest that Trk activation is not involved in the retinal effects of PACAP (Silveira et al., unpublished data). Finally, the widespread expression of several peptides and their receptors in developing retinal tissue suggests that neuropeptides may be more important for retinal development than currently realized, including their participating in the network of extracellular mediators involved in the control of sensitivity to PCD.

6. Conclusions and perspectives

Fig. 5. Neuroprotection by neuropeptides. The graphs show the rate of cell death in the NBL of retinal explants from neonatal rats, treated with 1 mg/ml anisomycin together with various concentrations of either PACAP27 (A) or VIP (B). From Silveira et al. (2002) and unpublished results.

We demonstrated that PACAP protects developing retinal tissue against induced cell death (Silveira et al., 2002). This was found using a histotypical explant culture system, in both post-mitotic undifferentiated cells and developing photoreceptors. We showed that this effect was dependent on an increase of cAMP levels and activation of PKA, and our results suggest that it is a direct effect of PACAP (Silveira et al., 2002). A similar cAMP-dependent neuroprotective effect seems to be exerted by VIP (Fig. 5 and M.S. Silveira et al., unpublished data). In summary, there is little data on effects of neuropeptides upon cell survival in the developing retina. Nonetheless, there is compelling evidence for a neuroprotective role of both PACAP and VIP (Kaiser and Lipton, 1990; Shoge et al., 1999; Silveira et al., 2002). These data have in common that the protective effects depend on an increase in the production of cAMP as well as, in some cases, activation of cAMPdependent protein kinase (PKA). This has also been found of neuroprotective effects described for other peptides in distinct regions of the nervous system, such as CRF for hippocampal neurons (Lezoualc’h et al.,

The control of programmed cell death in complex tissues such as the retina depends on a network of intercellular interactions. The pathway from tissue factors to cell demise may be roughly subdivided in three levels, those of extracellular mediators, intracellular signal transduction pathways and downstream execution pathways. Distinction between the latter 2 levels is somewhat arbitrary, and for the sake of the current argument, execution pathways are defined as downstream steps specifically linked to the commitment and irreversibility of cell death. Whereas the most common and best understood mechanism of execution of cell death is that of caspase-mediated apoptosis, current evidence clearly shows that not only there are many parallel pathways to apoptotic cell death, but also non-apoptotic programs of execution of cell death are available, and may be triggered either in isolation or combined with apoptosis (Guimara˜es and Linden, 2004, for review). The experimental data reviewed above also showed that many signaling pathways can modulate cell death. In some cases, elements of the execution pathways have been identified as proximal targets, such as the critical role of the cAMP–PKA pathway in the control of mitochondrial, caspase-dependent apoptotic cell death, through phosphorylation of the Bcl-2 family protein Bad (Harada et al., 1999), as well as the direct control of caspase activity by either phosphorylation (Allan et al., 2003) or nitrosylation (Torok et al., 2002). Among the various extracellular mediators, such as growth factors, that control programmed cell death via several signaling pathways, the data reviewed here highlighted the roles of neurotransmitters and

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neuromodulators. We focused upon developmental effects of these signaling molecules, particularly because of the evidence for anterograde neurotrophic control provided by experiments in a variety of models of the central nervous system, and on the evidence that an early function of extracellular signaling molecules within the developing nervous system is the trophic support of nerve cell populations, preceding the maturation of synapses. A rich experimental approach has provided ample evidence that both neurotransmitters and neuromodulators affect the sensitivity to cell death within the developing retina. This may have implications both regarding the mechanisms of retinal organogenesis, as well as pathological conditions leading to retinal dystrophies and to dysfunctional cellular behavior such as found in retinoblastoma. Nevertheless, at least three major points should be raised that stand at the edge of knowledge about the physiological role of neuroactive molecules in retinal development. First, whereas for some molecules, such as the neurotransmitters glutamate and dopamine, and the neuropeptides PACAP and VIP, there is compelling evidence for developmental effects upon the retina, for most other neuroactive substances the data are available only for adult retina, or in some cases, for other parts of the central nervous system. Still, in view of the expression of many neurotransmitter and neuropeptide systems in immature retinal tissues, investigation of possible similar roles for these other systems is warranted. Second, in most cases, the effects were detected using either indirect methods for evaluating cell death or specific apoptotic markers. Mounting evidence for alternative pathways of cell death raise the possibility that modulation of cell death by neuroactive substances may have been overlooked for want of alternative cell death markers (e.g. Munafo and Colombo, 2001). Third, in many studies the demonstration was in fact restricted to pharmacological effects of neuroactive molecules upon cell cultures, and it is still not known whether those cases reflect physiological roles upon developmental neuron death in the retina in vivo. Given that signal transduction pathways are shared by a variety of extracellular modulators, conclusions about the physiological role of each neuroactive molecule need deeper probing. Experimental loss-of-function approaches, such as pharmacological inhibition, transfection with dominant negative, non-signaling receptors, antisense, siRNA- and conditional knock-outs may help establish the role of neuroactive substances upon the control of developmental cell death in physiological context. In addition, the study of cellular responses related to the control of programmed cell death should be greatly enhanced by approaches that take into consideration the compartmentalization of signaling

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pathways, and their relationship to the compartmentalized cell death execution mechanisms. Notwithstanding, it is clear that neuroactive molecules such as classical neurotransmitters and neuromodulators are components of the network of intercellular interactions that control the sensitivity to cell death. This early role of neuroactive substances adds to the well-known role of growth factors such as the neurotrophins upon retinal development.

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