Nitric oxide neurons and neurotransmission

Progress in Neurobiology 90 (2010) 246–255

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Progress in Neurobiology journal homepage: www.elsevier.com/locate/pneurobio

Nitric oxide neurons and neurotransmission Steven R. Vincent * Department of Psychiatry & the Brain Research Centre, The University of British Columbia, Vancouver, BC, V6T 1Z3 Canada

A R T I C L E I N F O

A B S T R A C T

Article history: Received 30 November 2008 Received in revised form 22 April 2009 Accepted 9 October 2009

Nitric oxide was identified as a biological intercellular messenger just over 20 years ago, and its presence and potential importance in the nervous system was immediately noted. With the cloning of NO synthase and the physiological NO receptor soluble guanylyl cyclase, a variety of histochemical methods quickly led to a rather complete picture of where NO is produced and acts in the nervous system. However, the details regarding the subcellular localization of NO synthase and the identity of its molecular binding partners require further clarification. Although the hypothesis that calcium influx via activation of NMDA receptors is a key trigger for NO production has proven very popular and led to suggested roles for NO in synaptic plasticity, there is little direct evidence to support this notion. Instead, studies from the peripheral nervous system indicate a key role for voltage-sensitive calcium channels in regulating NO synthase activity. A similar mechanism may also be important in central neurons, and it remains an important task to identify the precise sources of calcium regulating NO production in specific NO neurons. Also, although cGMP production appears to mediate the physiological signaling by NO, the specific roles of cGMP-dependent ion channels, protein kinases and phosphodiesterases in mediating NO action remain to be determined. ß 2009 Elsevier Ltd. All rights reserved.

Keywords: Nitric oxide NADPH diaphorase Peripheral nervous system Central nervous system Sphenopalatine ganglion Enteric nervous system

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NO in the peripheral nervous system . . . . . . . . . . . . . . . . . . . . . . . . 2.1. NO in the innervation of the cranial blood vessels . . . . . . . . 2.2. The NO innervation of the penis . . . . . . . . . . . . . . . . . . . . . . 2.3. NO in the enteric nervous system and prevertebral ganglia. NO in the central nervous system. . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Nitric oxide in the cerebellum . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Nitric oxide in the reticular activating system . . . . . . . . . . . 3.3. Nitric oxide in the forebrain. . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Although nitric oxide has been known to have pharmacological actions for a great many years, the era of nitric oxide as an Abbreviations: AMPA, a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate; GABA, g-amino butyric acid; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; EDRF, endothelium-derived relaxing factor; LTS, low-threshold spike; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NMDA, N-methyl-D-aspartate; NO, nitric oxide; ODQ, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; PSD-95, post-synaptic density protein of 95kD; VIP, vasoactive intestinal peptide. * Tel.: +1 604 822 7038; fax: +1 604 822 7981. E-mail address: [email protected]. 0301-0082/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.pneurobio.2009.10.007

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endogenous messenger molecule began just over 20 years ago. It is perhaps timely therefore to review the current research on the neurobiology of this still rather unusual molecule. In 1987, Palmer et al. (1987) reported that the biological activity of the endothelium-derived relaxing factor of Furchgott (Furchgott and Zawadzki, 1980) could be accounted for by nitric oxide release; a major discovery quickly confirmed by others (Ignarro et al., 1987). A synthetic pathway for nitric oxide from arginine was soon identified (Palmer et al., 1988; Schmidt et al., 1988) and the age of nitric oxide biology begun. That nitric oxide might also play a key role in the nervous system was indicated by the exciting discovery that NMDA treatment of cerebellar cultures resulted in the formation of an

S.R. Vincent / Progress in Neurobiology 90 (2010) 246–255

EDRF-like factor (Garthwaite et al., 1988). This was quickly shown to be due to the arginine-dependent synthesis of nitric oxide (Bredt and Snyder, 1989; Garthwaite et al., 1989). With the subsequent cloning and characterization of neuronal NO synthase it was shown to be a calmodulin-dependent enzyme (Bredt et al., 1991). Together, these observations led to the extremely attractive hypothesis, first enunciated by Garthwaite et al. (1988) that ‘‘influx of Ca2+ through NMDA-linked channels represents a likely trigger for EDRF production’’. Although this hypothesis has generated much research and speculation, it must be noted that in these studies of cerebellar slices and cultures, neuronal activity was never blocked, for example with tetrodotoxin, and thus the mechanisms mediating NMDA or glutamate induced NO formation in these preparations are not clear. There were hints in the past for this novel biosynthetic pathway. For example, Deguchi and Yoshioka already in 1982 identified L-arginine as an endogenous activator of guanylyl cyclase (Deguchi and Yoshioka, 1982). In addition, studies by Ratner et al. (1960) had demonstrated many years ago that the enzymes required for the conversion of citrulline to arginine were expressed in the brain. It now appears that the NO synthase expressing neurons often express high levels of arginine, citrulline and the enzymes arginosuccinate synthase and lyase (Arnt-Ramos et al., 1992; Braissant et al., 1999; Isayama et al., 1997; Nakamura, 1997; Nakamura et al., 1991; Nakata et al., 1991; Pasqualotto et al., 1991; Shuttleworth et al., 1995; Yu et al., 1997a,b). This arginine– citrulline cycle may allow NO synthase neurons to maintain adequate levels of arginine for NO synthesis. NO is an ancient messenger molecule. Various bacterial forms of NO synthase have been identified (Adak et al., 2002a,b; Pant et al., 2002). These appear similar to mammalian NO synthase, but lack an essential reductase domain to supply electrons for NO synthesis, and instead use other cellular redox partners (Gusarov et al., 2008). In metazoans, the NO synthase structure is highly conserved. A sea urchin NO synthase gene has been described (Cox et al., 2001), and genes for a neuronal NOS and a soluble guanylyl cyclase described in mollusks (Fujie et al., 2005; Matsuo et al., 2008). Insect NO synthase has been well characterized (Imamura et al., 2002; Ohtsuki et al., 2008; Regulski and Tully, 1995; Yuda et al., 1996) and a similar crustacean NO synthase described (Kim et al., 2004). One curiosity is the clear lack of NO synthase in the C. elegans genome (Morton et al., 1999). Why this particular creature should get along fine without this otherwise ubiquitous messenger is a puzzle; perhaps it is just to frustrate geneticists interested in this novel messenger. NO synthase has been described in all vertebrates examined, including fish (Cox et al., 2001), amphibians, reptiles, birds, and mammals including primates. Vertebrates express three distinct isoforms of NO synthase that are highly homologous, yet have distinct structures, regulation and distribution (Stuehr, 1999). The neuronal form was the first to be cloned and characterized (Bredt et al., 1991), and appears to be the isoform responsible for NO production in neurons. Indeed the overall distribution of NO synthase in the nervous system of vertebrate species is generally well conserved. Support for the idea of a role for NMDA-dependent calcium influx in the regulation of neuronal NO synthase came from the observation that neuronal NO synthase differs from other NO synthase isoforms in possessing a 230 residue N-terminal region containing a Class III PDZ domain (Tochio et al., 1999). NO synthase and PSD95 were found to interact in the yeast two-hybrid assay, and could be co-immunoprecipitated from cerebellar membranes (Brenman et al., 1996). This has led to the suggestion that PSD95 molecules may form a complex at synapses anchoring NO synthase in close proximity to NMDA receptors. Although such a NMDAPSD95-neuronal NO synthase complex has been generated in

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transfected cell lines and shown to be functional (Ishii et al., 2006), it is not clear to what extent it exists or is functional in neurons. Indeed, a wide variety of other PDZ-dependent interactions with neuronal NO synthase have been reported (Chanrion et al., 2007; Firestein and Bredt, 1999; Hashida-Okumura et al., 1999; Jaffrey et al., 1998, 2002; Lemaire and McPherson, 2006; Manivet et al., 2000; Ort et al., 2000; Riefler and Firestein, 2001; Saitoh et al., 2004; Schuh et al., 2001; Stricker et al., 1997). An interesting recent project developed specific antibodies to the neuronal NO synthase b-finger domain mediating PDZ binding, and found that the overall distribution of immunolabeling obtained with the neuronal NO synthase b-finger antibody was very similar to that obtained with pan-neuronal NO synthase antibodies, indicating a lack of in situ PDZ-association and favoring a predominantly cytoplasmic distribution of NO synthase in various brain regions, including the hippocampus (Langnaese et al., 2007). Thus the extent to which neuronal NO synthase associates with various scaffolds and is targeted to specific subcellular domains remains an open question. The characterization of neuronal NO synthase led to the development of antibodies to this enzyme together with probes to detect the mRNA for this protein (Bredt et al., 1990). Furthermore, it was quickly shown that the NAPDH-diaphorase histochemical method provided a simple and specific technique with which to localize NO synthase (Hope et al., 1991). Together these various methods allowed the rapid determination of the distribution of NO synthase throughout the nervous system; the biochemical neuroanatomy of the NO system. These numerous studies have indicated that NO is produced in a wide variety of neurons of different types throughout the peripheral and central nervous systems (Aimi et al., 1991, 1993; Alm et al., 1993; Bredt et al., 1990; Burnett et al., 1993; Ceccatelli et al., 1994; Judas et al., 1999; Minami et al., 1994; Rodrigo et al., 1994; Vincent, 1994; Vincent and Kimura, 1992). These studies have also indicated that NO synthase can be found in the cell bodies, dendrites and axon terminals of neurons. 2. NO in the peripheral nervous system It might first be instructive to examine the peripheral nervous system in order to gain further insight into the regulation and actions of this novel messenger. In addition to being produced in endothelial cells as the EDRF by the endothelial form of NO synthase, NO is also a major messenger used by the peripheral nervous system (Vincent, 2000). Here it is produced by the neuronal form of the enzyme, although clearly, NMDA receptors do not mediate its formation. Instead, calcium influx through voltagegated ion channels, together with calcium release from intracellular stores are thought to trigger NO synthase activation. 2.1. NO in the innervation of the cranial blood vessels One area of great interest and importance is the innervation of the cerebral vasculature by NO neurons originating in the sphenopalatine ganglia (Fig. 1A–E) (Ceccatelli et al., 1994; Iadecola et al., 1993; Kimura et al., 1997; Minami et al., 1994; Morris et al., 1993; Nozaki et al., 1993; Suzuki et al., 1993; Uddman et al., 1999). In these neurons NO synthase coexists with the classical neurotransmitter acetylcholine and the peptide transmitter VIP (Fig. 1). Here, electrical stimulation of the nerves innervating the cerebral vessels produces an NO dependent relaxation that can be blocked by tetrodotoxin or an N-type calcium channel blocker (Toda et al., 1995). Indeed, N-type Ca2+ channels are the dominant voltage-dependent Ca2+ channels regulating Ca2+ influx during membrane depolarization of the NO synthase-positive sphenopalatine ganglion neurons (Liu et al., 2000) with R-type channels

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Fig. 1. Coexistence of choline acetyltransferase immunofluorescence (A), vasoactive intestinal polypeptide immunofluorescence (B) and NADPH diaphorase staining (C) of NO synthase in neurons in the rat sphenopalatine ganglion. NO synthase containing nerve fibers arising from these neurons heavily innervate the cerebral arteries (D and E) and the eye (F). Note the positive amacrine cells in the retina. The celiac ganglion receives a dense innervation (G) from the NADPH-diaphorase positive cells in the myenteric plexus. Following lesion of this input, a few of the positive fibers likely arising from sensory neurons and the sympathetic preganglionic neurons of the intermediolateral column remain (H).

contributing to a minor extent. Consistent with its role as the physiological NO receptor, inhibition of soluble guanylyl cyclase with ODQ (Garthwaite et al., 1995) prevented neurogenic relaxation (Gonzalez et al., 1997). 2.2. The NO innervation of the penis A similar situation appears to apply in the penis, where neurogenic relaxation was endothelium-independent and was inhibited by N-type Ca2+ channel antagonists (Okamura et al., 2001). Neurogenic NO activates soluble guanylyl cyclase and increases the generation of cyclic GMP in cavernosal muscle cells, resulting in the relaxation. NO synthase-positive postganglionic

parasympathetic nerves from the pelvic ganglia densely innervate cavernous tissues and penile arteries (Alm et al., 1993; Burnett et al., 1993; Dail et al., 1995; Keast, 1992; Schirar et al., 1994; Tamura et al., 1995). Many of these neurons also express VIP (Ehmke et al., 1995; Matsuda et al., 1996; Mizusawa et al., 2001; Tamura et al., 1995, 1997; Okamura et al., 2001). Again, inhibition of soluble guanylyl cyclase with ODQ prevented neurogenic relaxation (Recio et al., 1998; Simonsen et al., 2001). 2.3. NO in the enteric nervous system and prevertebral ganglia A large number of studies have demonstrated that NO synthase is expressed in populations of neurons throughout the gut (Alm

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et al., 1993; Anderson et al., 1995; Bredt et al., 1990; Ceccatelli et al., 1994; Costa et al., 1992; Dawson et al., 1991; Furness et al., 1994; Ward et al., 1992). It is found both in inhibitory motorneurons, and enteric interneurons (Yuan et al., 1995). This is consistent with work indicating that NO production may be responsible for relaxation of smooth muscle in the gut (Bayguinov and Sanders, 1993; Keef et al., 1993; Sanders and Ward, 1992; Shuttleworth et al., 1991). Muscle relaxation and NO release from enteric neurons can be evoked by field stimulation, and are blocked by tetrodotoxin or NO synthase inhibitors. NO synthesis in enteric neurons appears to be primarily dependent upon the influx of calcium via high-threshold calcium channels of the P, N and L variety (Kurjak et al., 2002). The prevertebral ganglia regulate a variety of visceral functions including digestive tract motility, secretion and absorption. The coeliac ganglion neurons receive a dense innervation of NO synthase fibers from the gut (Fig. 1G and H) that appears to regulate gut motility (Aimi et al., 1993; Furness and Anderson, 1994). This appears to be via the calcium-dependent production of NO and the formation of cGMP in the coeliac ganglion, where NO is released in response to splanchnic nerve stimulation (Quinson et al., 1999). Thus this again appears to be a useful model to examine NO production in response to activation of voltagesensitive calcium channels in nerve terminals. 3. NO in the central nervous system 3.1. Nitric oxide in the cerebellum The cerebellar cortex contains very high levels of NO synthase and NO production there appears to regulate functional hyperemia (Yang et al., 1999). NO synthase is expressed by local stellate, basket, and granule cells, but not Purkinje cells (Rodrigo et al., 1994; Vincent and Kimura, 1992). In an elegant study combining electrochemical NO detection with electrophysiology and imaging, Rancillac et al. (2006) confirmed that Purkinje cells do not express NO synthase. Instead they demonstrated that NMDA stimulation or direct depolarization of stellate cells in the molecular layer evoked NO release and local vasodilation. Interestingly, the NMDA evoked NO release was blocked by tetrodotoxin indicating that Ca2+ influx through the NMDA receptor may not be the trigger for NO production, and that spike firing of the stellate cells is required. High frequency stimulation of mossy fibers, which synapse on granule cells caused a significant NO release in the granular layer that was dependent on NMDA-receptor activation (Maffei et al., 2003). However, previous studies had shown that NO release in cerebellar slices in response to white matter stimulation presumably of parallel fibers was not affected by antagonists of NMDA receptors or other glutamate receptors (Kimura et al., 1998; Shibuki and Kimura, 1997) but was dramatically reduced by blockade of P/Q-type calcium channels (Shibuki and Kimura, 1997), and the cerebellar interneurons are known to express such channels (Stephens et al., 2001). In other words, a functional NMDA-receptor complex with NO synthase is not present in parallel fiber terminals (Shin and Linden, 2005). Instead, stellate and perhaps basket cells may mediate NMDA-dependent NO production. These interneurons express high levels of NO synthase (Fig. 2A) (Rodrigo et al., 1994; Vincent and Kimura, 1992) and NMDA receptors (Akazawa et al., 1994). Cerebellar NO also affects Purkinje cell function, in particular participating in the induction of the long-term depression of parallel fiber inputs (Casado et al., 2002; Ito, 1986; Lev-Ram et al., 1995; Levenes et al., 1998; Linden et al., 1995; Ogasawara et al., 2007; Shin and Linden, 2005). Purkinje cells express very high levels of soluble guanylyl cyclase (Bidmon et al., 2006; Ding et al., 2004; Gibb and Garthwaite, 2001; Giuili et al., 1994), type 1 cGMP-

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dependent protein kinase (El-Husseini et al., 1999; Schlichter et al., 1980) and G-substrate (Endo et al., 1999; Hall et al., 1999; Nairn and Greengard, 1983), a phosphorylation-dependent inhibitor of protein phosphatase 1 and 2A. Thus, it appears that the NMDA receptor/NO cascade involved in cerebellar long-term depression is localized to interneurons rather than parallel fibers and that NO formed in these interneurons, perhaps via calcium influx through P/Q type calcium channels then acts in Purkinje cells dendrites to produce long-term depression (Shin and Linden, 2005). 3.2. Nitric oxide in the reticular activating system The cholinergic neurons of the laterodorsal and pedunculopontine tegmental nuclei express very high levels of NO synthase (Fig. 2C and D) and project to the thalamus (Aimi et al., 1991, 1993; Bredt et al., 1990; Dun et al., 1994; Minami et al., 1994; Rothe et al., 1999; Sugaya and McKinney, 1994; Usunoff et al., 1999; Vincent, 2000; Vincent and Kimura, 1992). At the ultrastructural level, this appears to be localized predominantly in the cytoplasm often in association with the endoplasmic reticulum (Rothe et al., 1999). Cholinergic neurons in the laterodorsal tegmental nucleus prominently express NMDA-receptor subunit immunoreactivity (Inglis and Semba, 1996) and are excited by glutamate through NMDA receptors (Sanchez and Leonard, 1996). In addition, R-type calcium channels may also play a key role in regulating NO production in these neurons (Kohlmeier and Leonard, 2006). Electrical stimulation or NMDA application evokes NO release from the somatodendritic region of these cells (Leonard et al., 2001). Local infusion of NMDA into the laterodorsal tegmental nucleus evokes NO and cGMP production, which in turn appears to modulate the release of noradrenaline from the adjacent locus ceruleus (Kodama and Koyama, 2006). In the thalamus, which is known to receive a massive innervation from the laterodorsal tegemental nucleus, NO is released following electrical stimulation of the laterodorsal tegmental nucleus and this NO formation in dependent upon action potential firing in these neurons (Miyazaki et al., 1996; Williams et al., 1997). Furthermore, endogenous NO production in the thalamus varies with behavioural state, being high during wake and REM sleep, and low during slow-wave sleep (Williams et al., 1997). Indeed, there is evidence that the level of NO production in these neurons may regulate the sleep–wake cycle (Hars, 1999). The mechanisms mediating NO action in the thalamus are not yet clear. Thalamic neurons express very high levels of type II cGMP-dependent protein kinase (El-Husseini et al., 1995, 1999; Vincent, 2000) and IRAG (Inositol 1,4,5-trisphosphate receptor associated cGMP kinase substrate (Geiselhoringer et al., 2004). NO in the thalamus appears to regulate cGMP-dependent protein kinase activity (El-Husseini et al., 1998). This signal cascade may regulate the firing pattern of thalamic neurons across behavioural states (Cudeiro et al., 2000; Pape and Mager, 1992; Shaw et al., 1999; Yang and Cox, 2008) or the processing of sensory information (Alexander et al., 2006; Cudeiro et al., 1994; Leamey et al., 2001). 3.3. Nitric oxide in the forebrain Another area in which NO neurons have received a great deal of attention is the forebrain. A population of NO synthase interneurons is present in the striatum, and similar cells are also present throughout the cortex. In the striatum, the NO synthase cells are aspiny interneurons that comprise only a few percent of the striatal neuronal population (Fig. 2B). These cells are GABAergic and usually also produce somatostatin and neuropeptide Y (Dawson et al., 1991; Figueredo-Cardenas et al., 1996; Kubota and

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Fig. 2. (A) Strongly stained NADPH-diaphorase positive stellate cells lie in the molecular layer (M) of the cerebellar cortex above the Purkinje cell layer (P) which is unstained, and the granule cell layer (G) which is weakly stained. In primary cultures of the rat striatum the intensely stained aspiny interneurons which express NADPH diaphorase are seen scattered among the unstained medium spiny neurons (B). The intensely stained NADPH diaphorase positive cells of the laterdorsal and adjacent pedunculopontine tegmental nuclei are shown (C). In situ hybridization using an oligonucleotide probe for neuronal NO synthase also strongly labels the cells of the laterodorsal tegmental nucleus (D).

Kawaguchi, 1994; Selden et al., 1994; Vincent et al., 1983). A similar population of cells is seen in the cortex (Dawson et al., 1991; Gonchar and Burkhalter, 1997; Higo et al., 2007; Judas et al., 1999; Kubota et al., 1994; Kubota and Kawaguchi, 1994; Smiley et al., 2000) and hippocampus (Fuentealba et al., 2008; Jinno et al., 1999; Jinno and Kosaka, 2004; Nomura et al., 1997; Seress et al., 2002; Valtschanoff et al., 1993). These forebrain interneurons all appear to have a common embryologic origin within the medial ganglionic eminence, from which they migrate tangentially to the striatum, hippocampus and cerebral cortex (Fogarty et al., 2007; Marin et al., 2000; Reid and Walsh, 2002). Recordings from identified NO synthase interneurons in the striatum indicated that these cells exhibited a unique phenotype characterized by calcium-dependent low-threshold spikes (LTS cells) (Kawaguchi, 1993; Kawaguchi et al., 1995). The majority of striatal NO synthase neurons had no detectable immunoreactivity for any of the AMPA receptor subunits (Bernard et al., 1997; Kwok et al., 1997), and there is not yet any compelling evidence for NMDA receptors on these aspiny interneurons. The other striatal cells, including the fast-spiking GABA interneurons and the cholinergic interneurons together with the medium spiny output

neurons receive direct glutamate input from the cortex (Fino et al., 2008), however, it is not yet clear if that is the case for the LTS NO synthase interneurons. In the cortex, this type of aspiny interneuron also generates low-threshold calcium spikes (Deuchars and Thomson, 1995; Goldberg et al., 2004; Kawaguchi, 1993; Kawaguchi et al., 1995). Goldberg et al. (2004) recorded identified cortical neurons from transgenic mice expressing green-fluorescent protein under the control of the somatostatin promoter. They made extremely interesting observations that these cells have AMPA receptors, but lack NMDA responses. Instead, low-threshold calcium spikes are evoked upon synaptic activation, such that the cells act as a ‘‘global single spiking unit’’ producing a global calcium signal throughout the entire dendritic tree of the cell. These cells exhibit ‘statedependent calcium signaling’ and fire in two ways, in burst mode, depolarization mediated by AMPA-mediated EPSPs activates Ttype calcium channels, which propagate through the neuron to trigger a global rise in calcium and a burst of action potentials. In tonic mode, when most T-channels are inactivated, AMPAmediated depolarizations evoke global action potentials (Goldberg et al., 2004). In contrast, in pyramidal cells and other types of

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cortical neurons, NMDA-receptor activation, combined with other conductances results in spatially confined calcium signals. One might speculate that the global calcium signals in the NOS interneurons might allow them to respond globally to discrete depolarizing synaptic inputs, releasing NO throughout the entire cortical area in which their processes ramify. The study of NO in the hippocampus has produced conflicting results. There has been such a plethora of publications suggesting a role for NO in various models of synaptic plasticity (Bohme et al., 1991, 1993; Bon et al., 1992; Bon and Garthwaite, 2001; Boulton et al., 1995; Doyle et al., 1996; Haley et al., 1992; Holscher, 1999; Hopper and Garthwaite, 2006; Mizutani et al., 1993; Musleh et al., 1993; Ramos et al., 2002; Schuman and Madison, 1991, 1994; Wu et al., 1997), that this concept has entered the textbooks as a dogma. However, there are numerous studies that do not support any such role for NO (Bannerman et al., 1994a,b; Chetkovich et al., 1993; Cummings et al., 1994; Tobin et al., 1995). Indeed, the presence of NO synthase in hippocampal pyramidal cells itself has been controversial, most reports initially indicating that hippocampal expression was confined to interneurons (Bredt et al., 1990; Rodrigo et al., 1994; Valtschanoff et al., 1993; Vincent and Kimura, 1992). However, after modifying fixation parameters and other variables, some sort of staining could be obtained by some groups within the CA1 pyramidal neurons (Blackshaw et al., 2003; Burette et al., 2002). Others have invoked the presence of the endothelial form of NO synthase in these cells (Dinerman et al., 1994; Kantor et al., 1996; O’Dell et al., 1994), but again this has not been seen by others, who instead report that endothelial NO synthase expression in the hippocampus is clearly confined to the endothelial cells (Blackshaw et al., 2003; Demas et al., 1999; Hashiguchi et al., 2004; Seidel et al., 1997; Stanarius et al., 1997; Topel et al., 1998). It is of interest that endogenous NO production in the hippocampus varies with behavioural state (Vincent et al., 1998), as noted previously in the thalamus (Williams et al., 1997). This NO may derive from the terminals of the septohippocampal neurons, many of which express NO synthase (Pasqualotto and Vincent, 1991), and contribute to the characteristic theta rhythm of neuronal activity in the hippocampus during active wake and REM sleep states (Simon et al., 2006; Vanderwolf et al., 1977). NO synthase containing interneurons in the hippocampus may also contribute, and these give rise to a dense network of fibers which ramify in close proximity to both pyramidal cell dendrites and arterioles, and may thus be able to regulate local blood flow in response to neuronal activity (Lovick et al., 1999). Forebrain regions express high levels of cGMP-stimulated phosphodiesterase (Repaske et al., 1993; Van Staveren et al., 2003). In particular, we have found that the medium spiny striatonigral neurons express this enzyme, and it appears to provide a mechanism whereby NO from aspiny interneurons, acting via cGMP can regulate dopamine-stimulated cAMP production (Lin et al., 2009). The role cGMP-regulated phosphodiesterases plays in mediating other NO actions deserves further study. 4. Conclusions Nitric oxide remains a fascinating but puzzling messenger in the nervous system. Although NADPH-diaphorase histochemistry combined with immunohistochemistry and in situ hybridization have clearly delineated the cells which synthesize NO and those which express its receptor, soluble guanylyl cyclase, much remains unknown regarding the significance of this signaling system in the central nervous system. The peripheral nervous system may suggest some clues. In particular the role of voltage-gated calcium channels in regulating the calcium influx that triggers NO synthesis

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deserves further study. In addition, analogy with the regulation of cerebral and penile blood flow on the one hand, and gastric reflexes on the other, suggests that NO actions may be long-acting and state dependent. Indeed measurements of endogenous NO production in the brain support this sort of prolonged global action for NO in the nervous system. References Adak, S., Aulak, K.S., Stuehr, D.J., 2002a. Direct evidence for nitric oxide production by a nitric-oxide synthase-like protein from Bacillus subtilis. J. Biol. Chem. 277, 16167–16171. Adak, S., Bilwes, A.M., Panda, K., Hosfield, D., Aulak, K.S., McDonald, J.F., Tainer, J.A., Getzoff, E.D., Crane, B.R., Stuehr, D.J., 2002b. Cloning, expression, and characterization of a nitric oxide synthase protein from Deinococcus radiodurans. Proc. Natl. Acad. Sci. U.S.A. 99, 107–112. Aimi, Y., Fujimura, M., Vincent, S.R., Kimura, H., 1991. Localization of NADPHdiaphorase-containing neurons in sensory ganglia of the rat. J. Comp. 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