ErbB receptor signaling in astrocytes: A mediator of neuron-glia communication in the mature central nervous system

Neurochemistry International 57 (2010) 344–358

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ErbB receptor signaling in astrocytes: A mediator of neuron-glia communication in the mature central nervous system Ariane Sharif a,b,c,*, Vincent Prevot a,b,c a

Inserm, Jean-Pierre Aubert Research Center, U837, Development and Plasticity of the postnatal Brain, F-59000 Lille, France Univ Nord de France, F-59000 Lille, France c UDSL, Laboratory of Anatomy, School of Medicine, Place de Verdun, F-59000 Lille, France b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 1 December 2009 Received in revised form 29 March 2010 Accepted 18 May 2010 Available online 26 May 2010

Astrocytes are now recognized as active players in the developing and mature central nervous system. Each astrocyte contacts vascular structures and thousands of synapses within discrete territories. These cells receive a myriad of inputs and generate appropriate responses to regulate the function of brain microdomains. Emerging evidence has implicated receptors of the ErbB tyrosine kinase family in the integration and processing of neuronal inputs by astrocytes: ErbB receptors can be activated by a wide range of neuronal stimuli; they control critical steps of glutamate–glutamine metabolism; and they regulate the biosynthesis and release of various glial-derived neurotrophic factors, gliomediators and gliotransmitters. These key properties of astrocytic ErbB signaling in neuron-glia interactions have significance for the physiology of the mature central nervous system, as exemplified by the central control of reproduction within the hypothalamus, and are also likely to contribute to pathological situations, since both dysregulation of ErbB signaling and glial dysfunction occur in many neurological disorders. ß 2010 Elsevier Ltd. All rights reserved.

Keywords: ErbB1 EGF Growth factors Transactivation Astrocytes Neuron-glia communication Gliotransmitter

1. Introduction Abbreviations: 5-HT, 5-hydroxytryptamine or serotonin; 20-HETE, 20-hydroxyeicosatetraenoic acid; AD, Alzheimer’s disease; ADAM, a disintegrin and metalloproteinase; AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; AREG, amphiregulin; ATP, adenosine triphosphate; bFGF, basic fibroblast growth factor; BTC, betacellulin; CNS, central nervous system; CNTF, ciliary neurotrophic factor; COX, cyclooxygenase; cPLA2, calcium-dependent phospholipase A2; DA, dopamine; EGF, epidermal growth factor; EPGN, epigen; EREG, epiregulin; ERK, extracellularsignal regulated kinase; FSH, follicle-stimulating hormone; GABA, gamma aminobutyric acid; GFAP, glial fibrillary acidic protein; GGF2, glial growth factor-2; GJHC, gap-junction hemichannel; GLAST, glutamate/aspartate transporter; GLT-1, glutamate transporter 1; GnRH, gonadotrophin releasing hormone; GPCR, G proteincoupled receptors; HB-EGF, heparin binding-EGF; IGF-1, insulin-like growth factor-1; KOR, k opioid receptor; LH, luteinizing hormone; MANF, mesencephalic astrocytederived neurotrophic factor; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; mGluR, metabotropic glutamate receptor; MMP, matrix metalloproteinase; MPP+, 1-methyl-4-phenylpyridinium; MOR, m opioid receptor; NF-kB, nuclear factor-kB; NGF, nerve growth factor; NMDA, Nmethyl-D-aspartate; NOS-2, nitric oxide synthase-2 or inducible nitric oxide synthase; NRG, neuregulin; PAG, phosphate-activated glutaminase; PAI-1, type-I plasminogen activator inhibitor; PGE2, prostaglandin E2; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PLA2, phospholipase A2; Pro-TGFa, transforming growth factor a precursor; TACE, tumor necrosis factor a-converting enzyme; TGFa, transforming growth factor a; TGFb1, transforming growth factor b1; TH, tyrosine hydroxylase; t-PA, tissue-type plasminogen activator. * Corresponding authors at: Inserm U837, Baˆtiment Biserte, Place de Verdun, 59045 Lille Cedex, France. Tel.: +33 320 62 20 64; fax: +33 320 53 85 62. E-mail addresses: [email protected] (A. Sharif), [email protected] (V. Prevot). 0197-0186/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuint.2010.05.012

Data accumulated over the past twenty years have revealed that the development and function of the nervous system relies on an intimate dialog between neurons and astrocytes. Astroglial cells, which enwrap nerve endings throughout the central nervous system (CNS), were initially ascribed the housekeeping function of maintaining a viable nervous system environment for neurons. Critical functions of astrocytes include providing metabolic support for neurons; buffering excess potassium and neurotransmitters; promoting neuronal maturation, synaptogenesis and angiogenesis; and maintaining the blood-brain barrier (Wang and Bordey, 2008). This original view of astrocytes playing a supportive role in CNS function has been markedly revised with the discovery that astrocytes ‘‘sense’’ neuronal activity and in turn ‘‘respond’’ to neurons. Neuronal activity induces an increase in the intracellular calcium level in astrocytes both in vitro and in vivo. These calcium elevations induce the release of gliotransmitters such as glutamate, ATP or D-serine, which feedback on neurons by modulating neuronal excitability and synaptic transmission (Araque et al., 2000; Bains and Oliet, 2007; Gordon et al., 2005, 2009; Jourdain et al., 2007; Martineau et al., 2006; Panatier et al., 2006; Parpura and Haydon, 2000; Pascual et al., 2005; Zhang et al., 2003). Moreover, astrocytes participate in neurovascular coupling by

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matching neuronal activity to vascular tone through the release of vasoactive substances (Haydon and Carmignoto, 2006; Iadecola and Nedergaard, 2007; Straub and Nelson, 2007). Because astrocytes are continuously exposed to a wide range of neuronal stimuli, it is of great importance that astrocytes correctly integrate these extracellular signals to generate appropriate responses in order to be able to support the function of particular neuronal populations and territories. Emerging evidence has implicated receptors of the ErbB tyrosine kinase family in this process. Upon activation, ErbB receptors couple diverse external stimuli to internal signal transduction pathways, thereby contributing to the ability of a cell to respond correctly to its environment (Jones et al., 2006). Studies in rodents have shown that ErbB signaling controls fundamental aspects of astrocyte function. ErbB1 and ErbB2 receptors regulate the proliferation, survival and differentiation of astrocytes both in vitro (Schmid et al., 2003; Sharif et al., 2007, 2006) and in vivo (Ghashghaei et al., 2007; Wagner et al., 2006). Moreover, accumulating data have shown that astrocytic ErbB receptor signaling is involved in many aspects of neuronastrocyte interactions, from housekeeping functions (e.g., the uptake and metabolism of glutamate) to the dynamic sensing of neurotransmitters and neuromodulators and the release of neuroactive factors. In this review, we summarize our current understanding of the role of astrocytic ErbB signaling in neuronastrocyte communication and focus on data that may have significance for the pathophysiology of the mature CNS. Following the dynamics of the functional relationship between neurons and glia, we will describe the impact of neuronal factors on astrocytic ErbB signaling, the role of ErbB receptors in the clearance and metabolism of glutamate in astrocytes and then the involvement of ErbB signaling in glia-to-neuron communication. Subsequently, the neuron-glia interactions that take place within the hypothalamus will be reviewed in detail, as this system provides the only integrated example of both the neuron-to-glia and glia-to-neuron communication that are coordinated to control a single physiological function, reproduction. Finally, the pathophysiological implications of the dysregulation of astrocytic ErbB signaling in neurological disorders will be discussed. 2. ErbB receptors in astrocytes The ErbB receptor family (originally named because of their homology to the erythroblastoma viral gene product, v-erbB) consists of four receptor tyrosine kinases, ErbB1 (also termed epidermal growth factor (EGF) receptor), ErbB2, ErbB3 and ErbB4. These receptors are also called HER (human epidermal growth factor receptor) in humans. All family members have a similar structure, with an extracellular ligand-binding domain, a single transmembrane domain and a cytoplasmic protein tyrosine kinase domain. ErbB receptors bind several ligands, known as EGF-related peptide growth factors (Riese and Stern, 1998). Ligand-dependent

345

Fig. 1. The ErbB receptor family and their ligands. ErbB1 (or EGFR, epidermal growth factor receptor) and ErbB4 are fully functional receptors that possess an extracellular ligand-binding domain and a cytoplasmic protein tyrosine kinase domain and can function as homo- or heterodimers. In contrast, ErbB2 (or neu), which lacks a ligand-binding domain, and ErbB3, which is defective in its intrinsic tyrosine kinase activity (dashed lines), must heterodimerize with another member of the ErbB family for signal transduction. The different EGF-like growth factors exhibit different binding specificity towards ErbB receptors. While TGFa, EGF, amphiregulin, epigen, neuregulin-3 and neuregulin-4 are specific for a single member of the receptor family, the five other EGF-like ligands can bind two or three receptors.

activation of ErbB receptors results in homo- or heterodimerization, which stimulates the intrinsic tyrosine kinase activity of the receptors and triggers autophosphorylation of specific tyrosine residues within their cytoplasmic domain (Olayioye et al., 2000). The latter provides docking sites for downstream signaling molecules. Interactions between ErbB receptors involve both homo- and heterodimer formation and are defined by the specificity of the receptors for different EGF family members. ErbB3, which shares ligand-binding specificities with ErbB4, lacks intrinsic kinase activity and requires heterodimerization for signal transduction. In contrast, ErbB2 has no known ligand, and primarily functions to modulate the activity of ErbB1, ErbB3 and ErbB4. ErbB1 binds EGF, TGFa, and five other related ligands. ErbB3 and ErbB4 bind a large group of structurally related peptides collectively known as neuregulins (NRGs; also called heregulins, or HRGs) (Hynes and Lane, 2005) (Fig. 1). ErbB receptors are expressed in astrocytes in vitro and in vivo. However, the repertoire of astrocytic ErbB proteins differs according to the brain region and the animal species (Table 1). In rodents, cultured cortical astrocytes express ErbB1 and ErbB2, but lack detectable levels of the neuregulin receptors ErbB3 and ErbB4 (Dufour et al., 2009; Ma et al., 1999; Sharif et al., 2007, 2006). In contrast, rat and mouse hypothalamic astrocyte cultures express ErbB1, ErbB2 and ErbB4 (Dziedzic et al., 2003; Ma et al., 1999; Prevot et al., 2003b). We recently demonstrated that regional

Table 1 Expression of erbB receptor proteins in cerebro-cortical and hypothalamic astrocytes of the human and rodent brain. Cerebrocortical astrocytes Rodents

erbB1 erbB2 erbB3 erbB4

Hypothalamic astrocytes Human

In vitro

In vivo

In vitro

+ +

+

+ + +

Rodents In vivo

Human

In vitro

In vivo

In vitro

In vivo

+ +

+ + nd +

+ +

nd nd nd +

+ +

+

In vitro data were obtained from western blot experiments and/or immunocytochemistry on primary cultures. In vivo data were obtained on brain sections using immunohistochemistry or by monitoring reporter gene expression under the control of the erbB1 promotor. nd, not determined. References: Dufour et al. (2009), Duhem-Tonnelle et al. (2010), Dziedzic et al. (2003), Ma et al. (1997, 1999, 1994), Prevot et al. (2003b), Sharif et al. (2009, 2007, 2006), Sibilia et al. (1998).

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differences in the expression pattern of ErbB receptors also exist in astrocytes of the human brain (Sharif et al., 2009). While primary cultures of astrocytes derived from either adult or fetal human cerebral cortex express ErbB1, ErbB2 and ErbB3, human fetal hypothalamic astrocytes express ErbB1, ErbB2 and ErbB4. These data also revealed inter-species heterogeneity in the ErbB expression pattern in cerebrocortical astrocytes. While rodent cortical astrocytes lack neuregulin receptors, human cortical astrocytes express ErbB3, allowing them to respond to three additional ErbB ligands (i.e., neuregulin-1, neuregulin-2 and epiregulin). It can be speculated that the addition of ErbB3 receptors to cortical astrocytes during evolution may serve to increase the pleiotropism of ErbB signaling, providing increased opportunities for intracellular pathway coupling (Citri and Yarden, 2006). However, while the set of ErbB receptors expressed in hypothalamic astrocytes is well preserved between rodents and humans, there are differences in the receptor dimers that are recruited in response to ligands. Neuregulins activate ErbB4/ErbB2 heterodimers in rodent hypothalamic astrocytes (Ma et al., 1999; Prevot et al., 2003b). In contrast, human hypothalamic astrocytes respond to neuregulins by tyrosine phosphorylation of ErbB4, but show no ErbB2 or ErbB1 phosphorylation. This suggests that neuregulins exclusively activate ErbB4/ErbB4 homodimers in these cells (Sharif et al., 2009). Thus, differential recruitment of receptor dimers in cells that express the same set of ErbB receptors provides another level of regulation and increases the potential diversity of ErbB signaling outcome. In intact brain, astrocytes express a low level of ErbB receptors. In the cerebral cortex, ErbB1 expression has been reported in astrocytes of the mouse brain (Kornblum et al., 1998; Sibilia et al., 1998). In contrast, ErbB2 was not detected in rodent cortical astrocytes, whereas its expression was seen in neuronal cells of the cerebral cortex, as well as in white matter astrocytes and glial fibers along the pial surface (Gerecke et al., 2001; Kuhn and Miller, 1996; Miller and Pitts, 2000; Tokita et al., 2001). In humans, we and others failed to detect ErbB1 and ErbB2 immunoreactivity in astrocytes of the adult cerebral cortex (Bouvier-Labit et al., 1998; Duhem-Tonnelle et al., 2010; Feldkamp et al., 1999; Hiesiger et al., 1993; Hunter et al., 1995; Torp et al., 2007, 1991; Waha et al., 1996; Werner et al., 1988). However, in studies that compared ErbB immunoreactivity between normal and pathological situations, high levels of ErbB1 and ErbB2 were detected in rodent and human reactive astrocytes as well as in GFAP-positive elements within human glial tumors (Duhem-Tonnelle et al., 2010; Hiesiger et al., 1993; Nieto-Sampedro et al., 1988; Tokita et al., 2001; Torp et al., 2007, 1991). Interestingly, while ErbB1 and ErbB2 immunoreactivity was not seen in human adult cerebral cortex tissue sections in situ, they could be detected in primary astrocyte cultures prepared from the very same biopsies (Duhem-Tonnelle et al., 2010; Sharif et al., 2009). Altogether, these observations suggest that in the intact brain, cortical astrocytes express a very low level of ErbB1 and ErbB2, but that these receptors can be strongly upregulated under activated conditions, i.e., in culture or in pathological situations in vivo. In contrast, and in agreement with data obtained using primary human astrocyte cultures, we have demonstrated that astrocytes of the human cerebral cortex express ErbB3, but lack detectable ErbB4 expression in situ (DuhemTonnelle et al., 2010). However, ErbB4 immunoreactivity is seen in astrocytes within the hypothalamus of human adult post-mortem tissue (Prevot V., unpublished data). Notably, while most cortical astrocytes in the adult human brain expressed ErbB3, a small subpopulation of ErbB3-negative astrocytes was also seen (Duhem-Tonnelle et al., 2010), suggesting that heterogeneous populations of astrocytes (with regard to the repertoire of ErbB receptors expressed) co-exist not only in distinct regions of the brain but also within given brain areas. The complex interplay

between members of the ErbB family is an essential hallmark of this signaling, and the biological response of a cell to an EGF ligand is dependent on the repertoire of ErbB receptors that are expressed (Lenferink et al., 1998; Ma et al., 1999; Riese et al., 1996; Sharif et al., 2009). Therefore, the differential distribution and recruitment of ErbB receptors between distinct astrocyte populations upon ligand binding is likely to contribute to the many roles played by these receptors in the control of neuron-glia communication. 3. Neuron-to-astrocyte signaling through ErbB receptors 3.1. Activation of astrocytic ErbB1 signaling by stimuli linked to neuronal activity Astrocytes express a large number of neurotransmitter and neuromodulator receptors, including glutamatergic, GABAergic, adrenergic, purinergic, serotoninergic, muscarinic and peptidergic receptors (Hansson and Ronnback, 2004; Porter and McCarthy, 1997). These receptors are functionally coupled to intracellular signaling pathways such as activation of phospholipase C or adenylate cyclase. Moreover, several studies have shown that some of these receptors are also able to activate ErbB1 and its downstream signaling cascades in astrocytes. In addition to direct activation by its cognate ligands, ErbB1 can be indirectly activated by agonists of G protein-coupled receptors (GPCRs), a phenomenon referred to as transactivation (Peng, 2004). This mechanism provides a link between GPCR agonists and the ERK/MAPK signaling cascade, leading to DNA synthesis. Two transactivation mechanisms have been reported to date: (1) the ligand-independent, exclusively intracellular activation of ErbB1 and (2) the ligand-dependent activation of ErbB1 through extracellular release of ErbB1 ligands. In the latter mechanism, GPCR agonists trigger activation of zinc-dependent matrix metalloproteinases (MMP) of the ADAM (a disintegrin and metalloproteinase) family (Yong et al., 2001) that mediate ectodomain shedding of transmembrane EGF-like growth factor precursors and subsequent release of mature ligands (Gschwind et al., 2001). In astrocytes, activation of adrenergic, serotoninergic, glutamatergic and opioidergic receptors has been reported to transactivate ErbB1 (Table 2). 3.1.1. Adrenergic receptors Expression of most adrenergic receptor subtypes has been shown in cultured and dissociated astrocytes and in the intact CNS, where they modulate many astrocytic functions (Hertz et al., 2004). It was recently demonstrated in live mice that electrical stimulation of the locus coeruleus, which provides the sole source of noradrenaline to the cortex, induces rapid calcium increase in cortical astrocytes (Bekar et al., 2008), thereby demonstrating the in vivo ability of astrocytes to respond to adrenergic inputs. Dexmedetomidine, a a2-adrenergic agonist, induces ErbB1 transactivation in cultured mouse astrocytes. Activation of a2adrenoreceptors stimulates MMP-mediated ectodomain shedding and the subsequent release of heparin binding-EGF (HB-EGF), which then activates ErbB1 in a paracrine and/or autocrine manner (Li et al., 2008a; Peng et al., 2003). Transactivation of ErbB1 following dexmedetomidine exposure has also been reported in the adult mouse brain (Du et al., 2009). Low concentrations of dexmedetomidine have neuroprotective properties (Kuhmonen et al., 1997). Interestingly, direct application of dexmedetomidine is unable to induce ERK phosphorylation in primary cultures of cerebellar neurons while conditioned medium from dexmedetomidine-treated astrocytes is able to do so (Li et al., 2008a). Furthermore, a recent study has demonstrated that noradrenaline is able to induce the release of a neuroprotective factor, the chemokine MCP-1 (monocyte chemoattractant protein-1), from

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Table 2 ErbB transactivation by receptors for the main neurotransmitters and neuromodulators in astrocytes. Ligand

GPCR

Cell cultures

ErbB

Transactivation mechanisma

Signaling pathwayb

Biological outcome

Reference

Dexmedetomidine

a2 AR

Mouse astrocytes

erbB1

Gi; PKC; Src; MMP; HB-EGF release

ERK1/2; cfos; fosB

Li et al. (2008a), Peng et al. (2003)

Fluoxetine

5-HT2B

Mouse astrocytes

erbB1

[Ca2+]i; PKC; MMP

DHPG AMPA and tACPD

erbB1 erbB1 and erbB4 erbB1

Gi/o; CaM; b-arrestin2; MMP

ERKc

U69,593

KOR

Rat cortical astrocytes Rat hypothalamic astrocytes Immortalized and primary rat cortical astrocytes Immortalized rat cortical astrocytes

Gq MMP

DAMGO, morphine

mGluR5 mGluR5 and AMPA receptors MOR

ERK1/2; cfos; fosB ERK2

ERK phosphorylation in primary cultures of cerebellar neurons cPLA2 up-regulation

erbB1

MMP

ERK

Up-regulation of erbB1 and erbB2 mRNA levels erbB1 levels, proliferationc

Li et al. (2009, 2008b) Peavy et al. (2001) Dziedzic et al. (2003) Belcheva et al. (2003), Miyatake et al. (2009) Belcheva et al. (2003)

Abbreviations: AMPA, Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid; AR, adrenoreceptor; [Ca2+]i, intracellular calcium concentration; CaM, calmodulin; cPLA2, calcium-dependent phospholipase A2; DAMGO, [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin; DHPG, group I specific mGluR agonist (RS)-3,5-dihydroxyphenylglycine; ERK, extracellular-signal regulated kinase; GPCR, G protein-coupled receptor; HB-EGF, heparin-binding epidermal growth factor; KOR, k opioid receptor; MMP, matrix metalloproteinase; mGluR, metabotropic glutamatergic receptor; MOR, m opioid receptor; PKC, protein kinase C; tACPD, mGluR agonist 1S,3R-ACPD; U69,593, (5a,7a,8b)( )-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl) benzeneacetamide. a Proteins implicated in the activation of erbB receptors by GPCR ligands. b Intracellular signaling pathways activated downstream of erbB receptors (ERK, phosphorylation of ERK; cfos and fosB, up-regulation of mRNA and protein levels). c The consequences of erbB1 transactivation by MOR depend on the duration of stimulation. While short-term (1–10 min) activation of MOR stimulates the phosphorylation of ERK, long-term (1–2 h) treatment down-regulates erbB1 and inhibits EGF-stimulated ERK phosphorylation and proliferation.

astrocytes (Madrigal et al., 2009). These data suggest that the neuroprotective effects of adrenergic agonists could involve an astrocytic intermediacy and raise the possibility that transactivation of ErbB1 could be part of this mechanism. 3.1.2. Serotoninergic receptors Astrocytes in culture express functional 5-HT2B receptors (Kong et al., 2002; Sanden et al., 2000). Stimulation of the serotonin 5-HT2B receptor by fluoxetine transactivates ErbB1 in primary mouse astrocytes via a MMP-dependent mechanism and triggers the phosphorylation of ERK1/2 and the subsequent up-regulation of c-fos and fosB expression (Li et al., 2008b). This mechanism has been implicated in the chronic fluoxetine-induced up-regulation of calcium-dependent phospholipase A2 (cPLA2), which releases arachidonic acid from membrane-bound phospholipids (Li et al., 2009). Arachidonic acid and its metabolites have been implicated in numerous critical functions of astrocytes, including the regulation of glucose metabolism, gap junction coupling and modulation of the vascular tone (Haydon and Carmignoto, 2006; Iadecola and Nedergaard, 2007; Martinez and Saez, 1999; Straub and Nelson, 2007; Yu et al., 1993). However, the final biological outcomes of 5-HT2B-mediated activation of ErbB1 in astrocytes remain to be explored. 3.1.3. Glutamatergic receptors Activation of glutamatergic receptors induces phosphorylation of ErbB1 in rat cortical and hypothalamic astrocytes (Dziedzic et al., 2003; Peavy et al., 2001). This mechanism involves formation of multiprotein signaling complexes. In rat cortical astrocytes, activation of metabotropic glutamate receptor 5 (mGluR5) induces physical association of mGluR5 and ErbB1, phosphorylation of ErbB1 and downstream activation of ERK2 (Peavy et al., 2001). However, the mechanism underlying the transactivation of ErbB1 by mGluR5 has not been determined in this cell system. In rat hypothalamic astrocytes, concomitant activation of mGluR5 and AMPA receptors by tACPD and AMPA, respectively, results in the recruitment of both ErbB1 and ErbB4 receptors to the cell membrane, bringing the receptors (physically) closer to their respective membrane-bound TGFa and NRG ligands, and the phosphorylation of each ErbB receptor via a mechanism that requires processing of ErbB ligand precursors by matrix metallo-

proteinases (Dziedzic et al., 2003). The calcium-dependent activation of tumor necrosis factor a-converting enzyme (TACE) in response to glutamatergic inputs has been shown to play a key role in this process by catalyzing the proteolytic shedding of proTGFa (Lomniczi et al., 2006) (Fig. 2). Co-immunoprecipitation experiments have shown that ErbB1 and ErbB4 were physically associated with mGluR5 and the GluR2/3 subunits of the AMPA receptor in hypothalamic astrocytes. Moreover, coactivation of metabotropic and AMPA receptors increases the mRNA level of ErbB1 and ErbB2 (Dziedzic et al., 2003). This neuron-to-glia pathway involving both glutamate receptors and astrocytic ErbB proteins may represent a basic cell–cell communication mechanism used by the neuroendocrine brain to coordinate the activation of glutamatergic neurons and astroglial cells during postnatal sexual maturation (see Section VII). 3.1.4. Opioid receptors Opioids are known regulators of astrocytic proliferation (Sargeant et al., 2008). While morphine and other m opioid receptor (MOR) ligands consistently decrease DNA synthesis in cultured rodent astrocytes (Sargeant et al., 2008), stimulation of k opioid receptors (KOR) increases proliferation (McLennan et al., 2008). Both MOR and KOR are able to transactivate ErbB1 in astrocytes (Belcheva et al., 2003; Miyatake et al., 2009). Short-term (1–10 min) activation of MOR in rat cortical astrocytes triggers ErbB1 activation and subsequent ERK phosphorylation, via a MMPdependent mechanism, suggesting that shedding of EGF-like ligands from the plasma membrane may be involved in the ErbB1 transactivation process (Belcheva et al., 2003). However, prolonged MOR stimulation (1–2 h) induces ErbB1 internalization and downregulation, does not activate ERK and attenuates EGF-induced ERK phosphorylation and proliferation (Belcheva et al., 2003; Miyatake et al., 2009). While short-term activation of KOR also induces phosphorylation of ErbB1 and ERK, long-term activation of KOR fails to down-regulate ErbB1 and yields sustained ERK activation (Belcheva et al., 2003). Belcheva and colleagues have proposed that the differential effects of MOR and KOR on ErbB1 signaling depended on the recruitment of Ser/Thr kinases that mediate ErbB1 desensitization (Morrison et al., 1996, 1993). While the MOR-associated kinases induce a Ser/Thr phosphorylation pattern of ErbB1 that targets the receptors to lysosomes, and their

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Fig. 2. Glutamate transactivates ErbB receptors in rodent hypothalamic astrocytes. Concomitant activation of glutamatergic metabotropic (mGluR) and AMPA receptors (GluR) stimulates the activity of zinc-dependent matrix metalloproteinases (MMP) of the ADAM (a disintegrin and metalloproteinase) family, which catalyze ectodomain shedding of the pro-EGF ligands pro-TGFa and pro-NRG (Dziedzic et al., 2003). In particular, the processing of pro-TGFa has been shown to involve the metalloproteinase ADAM17, also known as TACE (tumor necrosis factor a converting enzyme) (Lomniczi et al., 2006). The subsequently released mature TGFa and NRG activate ErbB1/ErbB2 and ErbB4/ErbB2 heterodimers, respectively (Ma et al., 1999; Prevot et al., 2003b). Note that co-activation of glutamatergic receptors induces the recruitment of ErbB1, ErbB4 and their pro-ligands to the cell membrane, where multiprotein complexes form, as demonstrated by the direct physical association of glutamatergic and ErbB receptors (not shown) (Dziedzic et al., 2003). Glu, glutamate.

subsequent degradation, the kinases mobilized by the KOR pathway induce the phosphorylation of different Ser/Thr residues that does not induce down-regulation of the receptors (Belcheva et al., 2003). Therefore, both the subtype of opioid receptor and the duration of stimulation affect ErbB signaling and astrocyte responsiveness to ErbB ligands. 3.1.5. Other putative neuronal stimuli Experiments conducted in cell systems other than astrocytes have shown that ErbB1 can be activated by cholinergic inputs (Jiang et al., 2009; Kanda and Watanabe, 2007; Krieg et al., 2004; Montiel et al., 2007; Nakayama et al., 2002; Prenzel et al., 1999; Tsai et al., 1997; Xie et al., 2009) and membrane depolarization (Egea et al., 1999; Rosen and Greenberg, 1996; Zwick et al., 1997, 1999), two stimuli linked to neuronal activity. Astrocytes express cholinergic receptors (Porter and McCarthy, 1997) and respond in vivo in the cortex of the cat brain to electrical stimulation of cholinergic nuclei with hyperpolarization that is mediated through activation of muscarinic receptors (Seigneur et al., 2006). Moreover, the astrocyte-mediated clearance of extracellular K+ and glutamate released during neuronal activity produces a depolarization of the astrocytic membrane (De Saint Jan and Westbrook, 2005; Diamond et al., 1998; Ge and Duan, 2007; Luscher et al., 1998). Therefore, stimulation of cholinergic

receptors and membrane depolarization are two other mechanisms used by astrocytes to sense neuronal activity. However, the possible integration of these neuronal inputs by ErbB signaling in astrocytes still remains to be explored. 3.2. Does transactivation of ErbB1 by neuron-derived stimuli occur in astrocytes of the human brain? All of the aforementioned studies showing that astrocytic ErbB1 receptors are transactivated by stimuli linked to neuronal activity were conducted in rodents. Whether ErbB receptors can be activated by neurotransmitters and neuromodulators in astrocytes of the human brain remains to be determined. Nonetheless, human astrocytes express all the molecular components required for the release of mature EGF-related peptide ligands that can activate ErbB receptors in a paracrine and/or autocrine fashion. Indeed, cultured human astrocytes derived from the adult and fetal cerebral cortex and from the fetal hypothalamus express mRNA encoding all EGF ligands except AREG and NRG4 (i.e., EGF, TGFa, HB-EGF, BTC, EREG, EPGN, NRG1, NRG2 and NRG3), as well as the mRNA of the three zincdependent matrix metalloproteinases, MMP2, MMP9 and ADAM17 (Duhem-Tonnelle et al., 2010), which are involved in ectodomain shedding of ErbB ligands (Sanderson et al., 2006).

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Phorbol myristate, which stimulates the metalloproteinasedependent shedding of ErbB ligands (Montero et al., 2000; Pandiella and Massague, 1991; Prenzel et al., 1999), triggers tyrosine phosphorylation of ErbB1 and ErbB3 in cortical astrocytes and of ErbB1 and ErbB4 in hypothalamic astrocytes. Ectodomain shedding of pro-TGFa has been shown to be involved in phorbol myristate-induced ErbB1 activation (Sharif et al., 2009). Therefore, human astrocytes express the machinery allowing cross-communication between GPCR and ErbB signaling through transactivation mechanisms, raising the possibility that receptors for neurotransmitters and neuromodulators may transactivate ErbB receptors in astrocytes of the human brain. Notably, the large repertoire of EGF-like ligand transcripts detected in astrocytes may be used to increase the functional plasticity of the signaling network. Altogether, ErbB receptors integrate many extracellular stimuli linked to neuronal activity and appear to function as central signal relay elements, which then initiate downstream signal progression to the Ras/ERK pathway, resulting in the initiation or modulation of gene transcription. Although much of the biological outcomes of this neuron-to-glia communication mediated through activation of ErbB signaling still remain to be uncovered, the data accumulated so far suggest that such mechanisms may contribute to the elaboration of the astrocytic response to neuronal activity and hence modulate the feedback action of astrocytes on neuronal function. 4. Modulation of astrocyte excitability by ErbB1 signaling While astrocytes are electrically non-excitable cells in the sense that they are unable to generate action potentials, they possess a form of excitability based on variations of the intracellular calcium concentration in response to neurotransmitters. These astrocytic calcium dynamics induce the release of gliotransmitters, which can signal back to the neurons and modulate synaptic transmission (Araque et al., 2001; Volterra and Meldolesi, 2005). A study conducted by Morita and colleagues showed that treatment of cultured rat cortical astrocytes with exogenous EGF switched the pattern of calcium dynamics from calcium transients to calcium oscillation in response to glutamate. Moreover, when cultures were maintained for more than 5 days in growth factor-free medium, accumulation of autocrine ErbB1 ligands was sufficient to promote calcium oscillations in response to glutamate, suggesting that astrocytes are able to autonomously control their own pattern of calcium increase (Morita et al., 2005). Experiments conducted in hippocampal slice preparations have suggested that the intrinsic calcium oscillation in astrocytes influences the neuronal activity of neighboring neurons via glutamate release (Morita et al., 2003). By demonstrating that ErbB1 ligands regulate the glutamate-induced calcium dynamics in astrocytes, these experiments suggest that ErbB1 signaling may modulate the feedback regulation of neural circuits by glial cells. 5. ErbB signaling is involved in the regulation of glutamate metabolism in astrocytes One of the key functions of astrocytes is the re-uptake and metabolism of the glutamate that is released in the synaptic cleft during neuronal activity. Glutamate released from neurons is converted to glutamine by the astrocyte-specific enzyme glutamine synthetase. Glutamine is then released into the extracellular space, where it is taken up into neurons and reconverted to glutamate by phosphate-activated glutaminase (PAG). This mechanism is known as the glutamate–glutamine cycle (Hertz and Zielke, 2004). ErbB receptors have been shown to be involved in the regulation of key steps of this metabolic process (Fig. 3).

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Glutamate is taken up by astrocytes through two astrocytic glutamate transporters, GLAST (or EAAT1) and GLT-1 (or EAAT2). In primary rat cortical astrocytes, EGF and TGFa induce expression of GLT-1 and GLAST mRNA and protein, which is accompanied by increased glutamate transport activity (Suzuki et al., 2001; Zelenaia et al., 2000). EGF also increases expression of GLT-1 protein in spinal cord organotypic cultures (Zelenaia et al., 2000). Notably, although GLT-1 and GLAST similarly respond to ErbB1 ligands with increased expression and activity, distinct regulatory mechanisms underlie this effect: the EGF-induced GLT-1 upregulation involves the PI3K/Akt/NF-kB signaling, while PKC and MAPK/ERK signaling pathways are not required in this process (Zelenaia et al., 2000). In contrast, the EGF-induced up-regulation of GLAST expression requires activation of Ras/MAPK, PI3K and PKC (Suzuki et al., 2001). Moreover, whereas the two transporters require activation of PI3K for their regulation, the divergence in intracellular signaling occurs downstream of PI3K, since Akt stimulates GLT-1 expression without affecting GLAST expression (Li et al., 2006). Another parameter that seems to be important for the differential regulation of GLAST and GLT-1 expression by ErbB1 ligands is the duration of growth factor stimulation. While longterm treatment (7 days) with EGF induces both GLT-1 and GLAST expression (Zelenaia et al., 2000), shorter treatment (2 days) upregulates GLAST but does not alter the GLT-1 level (Suzuki et al., 2001). In light of these results, the duration of ErbB1 stimulation may thereby determine the nature of the intracellular signaling network activated by EGF and, hence, the final outcome on the regulation of glutamate transporter expression. Altogether, these studies show that the differential expression of GLAST and GLT-1 by ErbB1 ligands is tightly regulated by the pattern of intracellular signaling cascades activated. Within the adult CNS, both ErbB receptors and their ligands (Junier, 2000) and astrocytic glutamate transporters (Danbolt, 2001) are differentially distributed. Indeed, GLT-1 is the predominant glutamate transporter in adult tissues, while the expression of GLAST is restricted to a few regions (Danbolt, 2001). Moreover, GLT-1 and GLAST exhibit non-overlapping expression patterns in astrocyte populations (Regan et al., 2007). The intracellular signaling pathways initiated by activation of ErbB receptors depend on the identity of the ligand and the nature of the receptor dimers that are activated (Junier, 2000). Whether distinct patterns of ErbB receptors and ligands participate in the differential distribution of astrocytic glutamate transporters is unknown and may be an interesting issue to explore. Alternatively, ErbB1 may indirectly impact GLAST and GLT-1 expression through modulation of mGluR. In primary astrocyte cultures, EGF and TGFa significantly up-regulate mGluR3 and mGluR5 expression, which is accompanied by increased downstream signal transduction in response to mGluR agonists (Miller et al., 1995; Minoshima and Nakanishi, 1999; Yamaguchi and Nakanishi, 1998). On the other hand, the expression of GLAST and GLT-1 is differentially regulated by mGluR in rodent and human astrocytes. Activation of mGluR5 induces down-regulation of GLAST and GLT-1 protein expression, whereas stimulation of mGluR3 has the opposite effect on the protein level of both transporters (Aronica et al., 2003; Gegelashvili et al., 2000; Hazell et al., 2003). Therefore, in addition to their direct stimulatory effects on GLAST and GLT-1 expression through mobilization of downstream ErbB1 transduction pathways, ErbB1 ligands may also regulate the glutamate-uptake capacity of astrocytes by modulating the mGluR-dependent sensing of extracellular glutamate. After its uptake into astrocytes, glutamate is converted to glutamine by glutamine synthetase. Several studies have shown that EGF increases glutamine synthetase activity in rodent astrocyte cultures (Grove et al., 1996; Kazazoglou et al., 1996; Loret et al., 1989).

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Fig. 3. ErbB1 signaling regulates key components of the glutamate–glutamine cycle. After its release into the synaptic cleft, glutamate (Glu) is taken up by astrocytes via two transporters, GLAST and GLT-1. ErbB1 ligands (EGF and TGFa) stimulate the expression and activity of both transporters, albeit with distinct regulatory mechanisms (Suzuki et al., 2001; Zelenaia et al., 2000). ErbB1 ligands also stimulate the expression of glutamatergic metabotropic receptor (mGluR) 3 and mGluR5 (Miller et al., 1995; Minoshima and Nakanishi, 1999; Yamaguchi and Nakanishi, 1998), which have stimulatory and inhibitory actions on the expression of astrocytic glutamate transporters, respectively (Aronica et al., 2003; Gegelashvili et al., 2000; Hazell et al., 2003). However, whether ErbB1 ligands can indirectly impact GLAST and GLT-1 expression through their action on mGluR still remains to be demonstrated. After its uptake into astrocytes, glutamate is converted to glutamine (Gln) by glutamine synthetase (GS). EGF increases glutamine synthetase activity in astrocytes (Grove et al., 1996; Kazazoglou et al., 1996; Loret et al., 1989). Glutamine is then released into the extracellular space and is taken up by neurons, where it is reconverted to glutamate by phosphate-activated glutaminase (PAG). Because gap junction hemichannels (GJHC) are permeable to glutamate, ErbB1 ligands may regulate the release of this transmitter from astrocytes through their inhibitory action on the permeability and expression of GJHC (Morita et al., 2007; Ueki et al., 2001). The possibility for such a mechanism, however, remains to be explored.

Altogether, these data show that ErbB1 signaling regulates key components of the glutamate–glutamine cycle by modulating the capacity of astrocytes to uptake glutamate from the extracellular space and by stimulating the subsequent metabolism of this neurotransmitter. 6. Astrocyte-to-neuron signaling through ErbB receptors 6.1. Effect of ErbB signaling on the biosynthesis and release of neurotrophic/neuroprotective factors ErbB1 ligands are well known for their neurotrophic effects on several neuronal populations (Yamada et al., 1997). Numerous studies have shown that the neurotrophic effects of ErbB1 on specific neuronal populations are mediated by astrocytes (reviewed in Junier, 2000). In primary cultures of astrocytes from various brain regions, ErbB1 ligands are able to stimulate the synthesis and/or release of various factors with neurotrophic properties, including NGF (Yoshida and Gage, 1991), IGF-1 (Chernausek, 1993; Han et al., 1992), CNTF (Kamiguchi et al., 1995), TGFb1 (Lindholm et al., 1992) and bFGF (Araujo and Cotman, 1992; Galbiati et al., 2002; Kamiguchi et al., 1996; Moffett et al., 1998). The first evidence that astrocytes are involved in the neurotrophic effects of ErbB1 came from an in vitro study by

Morrison and colleagues, who showed that medium conditioned by astrocytes grown in the presence of EGF promotes the survival and stimulates the process outgrowth of rat subneocortical telencephalic neurons (Morrison et al., 1987). Since then, experiments have demonstrated that ErbB1 requires an astrocytic intermediacy to exert its full neurotrophic/neuroprotective effect on several neuronal populations. 6.1.1. Mesencephalic dopaminergic neurons EGF and TGFa stimulate neurite outgrowth, dopamine (DA) uptake and long-term survival of rat mesencephalic dopaminergic neurons in vitro (Alexi and Hefti, 1993; Casper et al., 1991; Engele, 1998; Knusel et al., 1990; Park and Mytilineou, 1992). EGF also attenuates the toxicity of the MPP+ (1-methyl-4-phenylpyridinium) dopaminergic neurotoxin on neurons (Park and Mytilineou, 1992). Another EGF ligand, HB-EGF, promotes the survival of tyrosine hydroxylase (TH)-positive neurons in vitro (Farkas and Krieglstein, 2002). In all of these studies, ErbB1 ligands were shown to stimulate the proliferation of glial cells, and their neurotrophic/ neuroprotective action was abolished when glial cells were eliminated using anti-mitotic and glial-toxic agents (Casper et al., 1991; Knusel et al., 1990; Park and Mytilineou, 1992). Consistent with a glial-mediated mode of action, an analysis of cfos expression in response to growth factors, as a means to identify

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their cellular targets, showed that TGFa induces Fos expression predominantly in glia (Engele and Schilling, 1996). Altogether, these data suggest that ErbB1 ligands are able to support the growth and survival of dopaminergic neurons by activating ErbB1 signaling in astrocytes and inducing the release of glial neurotrophic factors, the identity of which remains to be determined. In addition to the well-documented roles of ErbB1 ligands on dopaminergic neurons, a previous study has shown that GGF2, an isoform of the NRG1 gene, also exerted neurotrophic/ neuroprotective actions on these neurons. As the glial contamination of cultures was extremely low, this study suggested that the neurotrophic effects of GGF2 on dopaminergic neurons were not mediated by mesencephalic astrocytes (Zhang et al., 2004). These observations raise the intriguing possibility that distinct EGF-like ligands exert neurotrophic/neuroprotective actions on mesencephalic dopaminergic neurons with different requirements for an astrocytic intermediacy. 6.1.2. Cerebrocortical neurons Another neuronal population affected by ErbB1 signaling in astrocytes is present in the cerebral cortex. Cortical astrocytes depend on ErbB1 signaling for their survival. Indeed, TGFa increases the in vitro lifespan of mouse cortical astrocytes and protects them from staurosporine-induced death (Sharif et al., 2006). Moreover, primary cortical astrocyte cultures derived from ErbB1-deficient mice show increased apoptosis (Wagner et al., 2006). When neurons are co-cultured with ErbB1-deficient cortical astrocytes, most of them die; in contrast, neurons survive in the presence of wild-type cortical astrocytes. Therefore, disruption of ErbB1 signaling in cortical astrocytes abolishes their ability to support neuronal survival in vitro. Interestingly, while midbrain astrocytes express the levels of both ErbB1 receptors and ligands comparable to those in cortical astrocytes, they are not dependent on ErbB1 signaling for their survival; ErbB1-deficient midbrain astrocytes are fully capable of keeping neurons alive (Wagner et al., 2006). In vivo, mice lacking ErbB1 develop selective neurodegeneration of the frontal cortex and olfactory bulbs, while other parts of the brain are unaffected (Kornblum et al., 1998; Sibilia et al., 1998). Interestingly, in contrast to cortical astrocytes, cortical neurons do not depend on ErbB1 signaling for their survival as ErbB1-deficient neurons survive very well when co-cultured with wild-type astrocytes or when cultured in neurobasal/B27 medium, which promotes the survival of neurons in the absence of astrocytes (Wagner et al., 2006). Altogether, these data indicate that the massive neurodegeneration that takes place in the cortex of ErbB1-deficient mice is a direct consequence of the disruption of ErbB1 signaling in astrocytes. In order to identify astrocyte-derived factors that are regulated by ErbB1 signaling and support the survival of cortical neurons, the expression level of a panel of astrocyte-derived neuroprotective factors was assessed in ErbB1-deficient cortical astrocytes compared to wild-type astrocytes. These experiments demonstrated that the expression of many neurotrophins and their receptors is not altered in ErbB1-deficient cortical astrocytes (Wagner et al., 2006). Therefore, the neuronal loss in ErbB1deficient mice is likely due to the increased apoptosis of mutant cortical astrocytes, which are no longer able to provide sufficient concentrations of neurotrophic factors to support the survival of neurons, rather than lack of specific neurotrophic factors. Therefore, activation of ErbB receptors on astrocytes exerts neurotrophic/neuroprotective actions on specific neuronal populations. Although these neurotrophic/neuroprotective effects were studied in a developmental context, they may have significance in the mature CNS, since mesencephalic dopaminergic neurons and cortical neurons are the targets of neurodegeneration in Parkinson’s disease and other neurodegenerative human disorders.

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6.2. Effect of ErbB signaling on the biosynthesis and release of gliomediators Excitation of astrocytes by neuronal inputs induces the release of gliomediators, which are chemicals that act on adjacent neurons, glial cells and vessels. Some of these glia-derived chemicals, including glutamate, ATP, adenosine and D-serine, have been shown to modulate synaptic transmission and neuronal excitability, and have been termed ‘‘gliotransmitters’’ (Araque et al., 2000; Bains and Oliet, 2007; Gordon et al., 2005, 2009; Jourdain et al., 2007; Martineau et al., 2006; Panatier et al., 2006; Parpura and Haydon, 2000; Pascual et al., 2005; Zhang et al., 2003). Eicosanoids (e.g., prostaglandins and 20-hydroxyeicosatetraenoic acid (20HETE)) are additional glial-derived mediators that have been implicated in neurovascular coupling by controlling the cerebral microcirculation (Haydon and Carmignoto, 2006; Iadecola and Nedergaard, 2007; Straub and Nelson, 2007). ErbB signaling may be involved in the regulation of gliotransmitter release, and accumulating data suggest that it is a key component in the communication mediated by prostaglandins. Astrocytes can release glutamate by two main mechanisms: exocytosis and non-exocytotic release through channels and transporters (Malarkey and Parpura, 2008). Among the plasma membrane channels thought to participate in the non-exocytotic release of glutamate are the gap-junction hemichannels (GJHCs), which are formed by hexamers of connexin 43 (Ye et al., 2003). Additionally, opening of astrocytic hemichannels can mediate release of ATP (Kang et al., 2008). Evaluation of GJHC activity by measurement of fluorescent dye leakage in cultured astrocytes and in hippocampal slice culture preparations has demonstrated that EGF inhibits GJHC activity within a short delay (10 min) without affecting the expression of connexin 43 (Morita et al., 2007). Longterm (48 h) treatment of cortical astrocytes with EGF induces down-regulation of connexin 43 at both the mRNA and protein level (Ueki et al., 2001). These results raise the possibility that ErbB1 signaling may participate in the regulation of gliotransmitter release via its modulatory action on GJHC permeability and expression. A gliomediator whose synthesis and release is regulated by the ErbB receptor family is prostaglandin E2 (PGE2). PGE2 is one of the main signals that is thought to mediate neurovascular coupling by astrocytes. Elevation of intracellular calcium concentration in astrocytes in response to neuronal activity can lead to activation of phospholipase A2 (PLA2), resulting in the production of arachidonic acid. Arachidonic acid can be metabolized by a host of different enzymes to generate vasodilating or vasoconstricting agents (reviewed in Haydon and Carmignoto, 2006; Iadecola and Nedergaard, 2007; Straub and Nelson, 2007). Prostaglandins are generated by cyclooxygenase (COX)-mediated metabolism of arachidonic acid and have been implicated in arteriole vasodilatation induced by neuronal activity (Zonta et al., 2003). In rat optic nerve astrocytes, EGF causes rapid induction of COX-2 protein expression and PGE2 release into the culture medium via an ERKand p38-dependent pathway (Zhang and Neufeld, 2005, 2007). In hypothalamic astrocytes, both ErbB1 and ErbB4 ligands (EGF/TGFa and NRGs, respectively) stimulate PGE2 release (Ma et al., 1997, 1999; Prevot et al., 2003b). This effect is mediated by the recruitment of ErbB1/ErbB2 heterodimers by TGFa and activation of ErbB4/ErbB2 heterodimers by NRGs, as disruption of ErbB2 expression inhibits both TGFa- and NRG-induced PGE2 release (Ma et al., 1999). Both ErbB ligands act in synergy, as low, ineffective doses of TGFa or NRGs trigger PGE2 release when these ligands are applied together (Ma et al., 1999). ErbB-induced PGE2 release is a key component in mechanisms controlling the function of neurons releasing gonadotropin-releasing hormone (GnRH). Indeed, the culture medium of hypothalamic astrocytes treated

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with EGF, TGFa or NRGs stimulates the release of GnRH from GnRH-producing GT1-1 cell line. In contrast, direct exposure of GT1-1 cells to ErbB ligands is ineffective in eliciting GnRH release (Ma et al., 1997, 1999). Therefore, ErbB ligands stimulate the secretory activity of GnRH-producing neurons via astroglialdependent, ErbB-mediated activation of PGE2 synthesis. Importantly, PGE2 was recently reported to directly modulate electrical activity of GnRH neurons. Indeed, patch-clamp recordings of GnRH neurons in slice preparations from adult mice showed that PGE2 exerts a powerful and direct excitatory effect on GnRH neurons via a postsynaptic EP2 PGE2 receptor (Clasadonte et al., 2009). This effect was abrogated when the metabolism of astrocytes was impaired by treatment of slices with fluoroacetate, suggesting that astrocytes could be the main endogenous source for PGE2. GnRH neurons from transgenic mice with targeted disruption of ErbB4 expression in astrocytes exhibited a significant reduction in their firing rate, which was rescued by exogenous addition of PGE2 (Clasadonte et al., 2009). Altogether, these data suggest that the activation of ErbB signaling in hypothalamic astrocytes stimulates release of PGE2, which has the capacity to modulate electrical activity of GnRH neurons and can therefore be considered a gliotransmitter. Thus, ErbB signaling in astrocytes has been implicated in the distinct dynamics of astrocyte-to-neuron communication. Stimulation of this signaling system exerts long-term neurotrophic/ neuroprotective actions on specific neuronal populations. This signaling system may also participate in dynamic neuron-glia communication, based on the timescale of neuronal activity, by modulating the biosynthesis and release of PGE2 and possibly other gliotransmitters. 7. The neuron-glia interactions involved in the hypothalamic control of reproduction require astroglial ErbB signaling Astroglial cells play key roles in the regulation of hormonal secretion by hypothalamic neurons (Garcia-Segura and McCarthy, 2004; Hatton, 1997; Ojeda et al., 2006; Prevot et al., 2007; Theodosis et al., 2006). Using a combination of in vitro and in vivo studies, the group of S.R. Ojeda demonstrated that ErbB signaling in hypothalamic astrocytes is central to the neuron-to-glia and gliato-neuron communication that regulates secretion of GnRH, the neurohormone controlling both sexual development and adult reproductive function. Glial ErbB signaling is also involved in cell plasticity and may control neurovascular junction formation (Fig. 4). Reproductive function requires the coordinated and timely activation of GnRH-producing neurons (Herbison and Neill, 2006; Ojeda et al., 2002). These neurons, which in rodents are located in the preoptic region of the hypothalamus, extend their neurosecretory axons to the median eminence of the hypothalamus, where GnRH is released into the pituitary portal blood vessels for delivery to the anterior pituitary gland. Within the adenohypophysis, GnRH induces the secretion of luteinizing hormone (LH) and folliclestimulating hormone (FSH), which in turn promote gonadal development and support reproductive physiology. Initiation of mammalian puberty is determined by an increase in pulsatile secretion of GnRH. This increase is brought about by coordinated changes in transsynaptic and glial-neuronal communication (Ojeda et al., 2003). These changing inputs appear to consist of three major interrelated events: a decrease in transsynaptic inhibitory tone, an increase in glutamatergic stimulation of GnRH neurons and activation of a glia-to-neuron signaling pathway. ErbB receptors expressed on hypothalamic astrocytes coordinate enhanced glutamatergic neurotransmission and astroglial feedback signaling to GnRH neurons (Ojeda et al., 2000). Indeed, combined activation of ionotropic and metabotropic glutamate

Fig. 4. Schematic representation of the neuron-glia interactions involved in the control of GnRH neurosecretion in the median eminence of the hypothalamus. Glial-neuronal interactions in the median eminence involve the production of the epidermal growth factor (EGF)-related peptides, TGFa and neuregulins (NRGs), by tanycytes and astrocytes. Binding of TGFa to tanycytic and/or astrocytic ErbB1 receptors, as well as binding of NRGs to astrocytic ErbB4 receptors, results in the recruitment of ErbB2 co-receptors and signal transduction. The ErbB-mediated downstream signaling leads to the secretion of bioactive molecules, such as prostaglandin E2 (PGE2), which are able to directly stimulate the releasing activity of GnRH nerve endings. In addition, ligand-dependent activation of ErbB1 receptors in tanycytes results in biphasic plastic changes that are characterized by an initial outgrowth phase and a secondary retraction phase. Although the initial outgrowth is independent of the TGFb1 system, the subsequent retraction requires PGE2 synthesis, a PGE2-dependent increase in the production of TGFb1 and matrix metalloproteinase (MMP) activity. Adapted from Prevot (2002) with permission.

receptors located on astroglial cells enhances the functional capability of astrocytic ErbB signaling modules by favoring, within a short time frame, the redistribution of TGFa-ErbB1 and NRGErbB4 complexes to the cell membrane and subsequent MMPdependent transactivation of receptors. Furthermore, over a longer time frame, activation of both ionotropic and metabotropic glutamate receptors by AMPA and tACPD, respectively, induces a selective increase in ErbB1 and ErbB2 receptor gene expression (Table 2; Dziedzic et al., 2003). Notably, the level of ErbB4 mRNA within the hypothalamus also increases during the peripubertal period in response to rising circulating level of estradiol (Ma et al., 1999). The metalloproteinase TACE releases TGFa from its transmembrane precursor and is involved in the glutamatergicmediated transactivation of ErbB1 in hypothalamic astrocytes (Lomniczi et al., 2006). Within the hypothalamus, TACE is most abundantly expressed in astrocytes of the median eminence, and its enzymatic activity increases selectively in this region at the time of the first preovulatory surge of gonadotropins. In vivo inhibition of TACE activity targeted to the median eminence delays the onset of female puberty, suggesting that TACE-mediated

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ectodomain shedding of TGFa is a key component of the neuronto-glia signaling mechanism underlying the advent of puberty (Lomniczi et al., 2006). Activation of ErbB signaling in hypothalamic astrocytes induces release of PGE2, which then controls the secretion of GnRH into the hypothalamic-adenohypophyseal portal system from GnRH nerve terminals (Ma et al., 1997, 1999). The integrity of ErbB signaling is crucial for the timing of puberty, since in vivo alteration of TGFa/ ErbB1 signaling (Apostolakis et al., 2000; Junier et al., 1991; Ma et al., 1992; Prevot et al., 2005) and ErbB2 receptors (Ma et al., 1999) impairs the onset of female puberty. Importantly, the selective disruption of ErbB4 signaling in astrocytes delays sexual maturation and leads to deficits in reproductive capacity in early adulthood (Prevot et al., 2005, 2003b). In vitro, ErbB1- and ErbB4deficient hypothalamic astrocytes are unable to induce secretion of PGE2 and subsequent release of GnRH (Prevot et al., 2005, 2003b). Therefore, these results suggest that the major reproductive defects seen in animals with impaired ErbB signaling are a consequence of the decreased ability of glial cells to stimulate GnRH release. Moreover, ErbB1 and ErbB4 work in a coordinated fashion to control reproductive function, since mutant mice with both disrupted ErbB1 and ErbB4 signaling exhibit further delay in the onset of puberty and a strikingly diminished adult reproductive capacity in comparison to mice deficient in either ErbB1 or ErbB4 alone (Prevot et al., 2005). Although the involvement of astrocytic ErbB signaling is now well established in neuron-glia communications that control reproductive function in rodents, it remains to be determined whether such a signaling system also underlies the central control of reproduction within the human brain. We recently demonstrated that cultured human hypothalamic astrocytes express the same repertoire of ErbB receptors as rodent hypothalamic astrocytes and that these receptors can be activated through MMP-dependent transactivation mechanisms (Sharif et al., 2009). An examination of the anatomical relationship between GnRH neurons and glial cells within the hypothalamus of women showed tight morphological interactions between GnRH neurons and astrocytes (Baroncini et al., 2007). Moreover, increased TGFa-ErbB1 signaling has been implicated in the etiology of precocious puberty induced by hypothalamic tumors (Jung et al., 1999). Altogether, these data support the hypothesis that astroglial ErbBs may also contribute physiologically to the control of GnRH neurons in the human neuroendocrine brain. In addition to being involved in communication processes between astrocytes and GnRH neurons, glial ErbB signaling may also account for part of the plastic remodeling that takes place at the neurovascular junction during the ovarian cycle (Prevot et al., 2007). Within the projection field of GnRH neurons (the median eminence of the hypothalamus), GnRH nerve terminals are tightly associated with glial processes belonging to specialized ependymoglial cells, known as tanycytes (Baroncini et al., 2007; King and Letourneau, 1994; Prevot, 2002). Under conditions of low gonadotropin output, the GnRH neurosecretory axon terminals are completely surrounded or engulfed by tanycytes, which prevent direct access to the vascular wall, thereby creating a diffusion barrier to GnRH entering the pituitary portal circulation. During the preovulatory surge, a structural remodeling occurs in tanycytes, which results in the release of the engulfed axons and formation of direct neurovascular contacts for GnRH neurons. The use of primary cultures of tanycytes from the median eminence as a model system has demonstrated that these cells express functional ErbB1 and ErbB2 receptors, but lack ErbB4 (Prevot et al., 2003a). Like hypothalamic astrocytes, tanycytes respond to ligand-promoted ErbB1 activation with release of PGE2. Median eminence tanycytes also release transforming growth factor beta 1 (TGFb1) which is a growth factor that has been previously

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implicated in the glial control of GnRH secretion (Bouret et al., 2004; Melcangi et al., 1995; Prevot, 2002). Ligand-dependent activation of ErbB1 receptors in tanycytes results in biphasic plastic changes characterized by an initial outgrowth phase and a secondary retraction phase. Although the initial outgrowth is independent of the TGFb1 system, the subsequent retraction requires PGE2 synthesis, a PGE2-dependent increase in the production of TGFb1 and matrix metalloproteinase activity. These in vitro results demonstrate that activation of ErbB1-mediated signaling in tanycytes results in plastic changes that, involving PGE2 and TGFb1 as downstream effectors, mimic the morphological plasticity displayed by tanycytes at the GnRH neurovascular junction during the hours encompassing the preovulatory surge of GnRH (Prevot, 2002). Therefore, the ErbB signaling system is a key component of the dynamic neuron-glia communication pathways used by hypothalamic astrocytes. These astrocyte-associated pathways facilitate GnRH secretion through the release of substances that promote cell plasticity and/or act directly on GnRH neurons to stimulate neurosecretion. 8. Pathophysiological implications It has become increasingly clear that astrocytes play a significant role in the pathogenesis of many neurological disorders including neurodevelopmental and neurodegenerative diseases (see Iadecola, 2004; Seifert et al., 2006; Volterra and Meldolesi, 2005 for review). Furthermore, ErbB receptors have been recently implicated in the pathophysiology of at least three of these disorders: schizophrenia, Alzheimer’s disease and Parkinson’s disease. NRG1/ErbB signaling has been genetically and functionally implicated in schizophrenia (Benzel et al., 2007; Buxbaum et al., 2008; Corfas et al., 2004a; Law et al., 2007). The gene that encodes NRG1 has been identified as a potential susceptibility gene for this disease, and defects in the expression of ErbB3 have been shown in the prefrontal cortex of schizophrenic patients (Hakak et al., 2001; Tkachev et al., 2003). Moreover, impairment of NRG-ErbB4 signaling has been implicated both in the NMDA receptor hypofunction (Hahn et al., 2006; Li et al., 2007) and white matter defects (Roy et al., 2007) that occur in schizophrenic patients. Although studies on the dysfunction in ErbB signaling have focused on neurons and oligodendrocytes, accumulating data has suggested that astrocytes may also contribute to the pathogenesis of schizophrenia (Cotter et al., 2001; Kondziella et al., 2007). As we have shown that human cortical astrocytes express ErbB3 receptors and can convey NRG1 signaling (Duhem-Tonnelle et al., 2010; Sharif et al., 2009), it would be interesting to explore whether dysregulation of NRG1/ErbB3 signaling also occurs in astrocytes of schizophrenic patients and whether this dysregulation may contribute to the development of schizophrenia. Dysregulation of ErbB4 signaling may also be involved in Alzheimer’s disease (AD), since presenilin, which is altered in this neurodegenerative disease, has been implicated in the proteolytic cleavage of transmembrane ErbB4 and downstream signaling to the nucleus (Sardi et al., 2006). Moreover, ErbB4 is expressed by reactive astrocytes and microglia surrounding neuritic plaques in the hippocampus of brains from patients with AD (Chaudhury et al., 2003). However, while glial dysfunction has been reported in this disease (Rodriguez et al., 2009), the putative implications of impaired ErbB signaling in astrocytes remain to be examined in AD. In patients with Parkinson’s disease, the expression of EGF, ErbB1 and ErbB2 is decreased in the prefrontal cortex and the striatum. Exogenous administration of EGF to the striatum in a rat model of Parkinson’s disease prevented local dopaminergic neurodegeneration (Iwakura et al., 2005). These results suggest that the impaired neurotrophic action of EGF on dopaminergic

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neurons may participate in the development of Parkinson’s disease. The body of data reviewed here shows that the neurotrophic and neuroprotective actions of ErbB1 signaling on midbrain dopaminergic neurons are mediated by astrocytes, suggesting that impairment of ErbB1 signaling in mesencephalic astrocytes may be involved in the dopaminergic neurodegeneration that takes place in Parkinson’s disease. The recent demonstration that administration of a neurotrophic factor derived from mesencephalic astrocytes (mesencephalic astrocyte-derived neurotrophic factor, MANF) exerts neurorestorative effects, even when injected four weeks after inducing a striatal lesion in an experimental model of Parkinson’s disease in rats (Voutilainen et al., 2009), raises the possibility that stimulation of the ErbB1dependent neurotrophic properties of mesencephalic astrocytes may have a significant therapeutic potential for the treatment of Parkinson’s disease. Neurodegenerative diseases and CNS trauma are systematically accompanied by astrogliosis. This process is characterized by profound changes in astrocytes, which pass from a quiescent to reactive morphology and metabolic profile (Ridet et al., 1997). Overexpression of the four ErbB receptors has been reported in reactive astrocytes both in rodent models and in human tissues (Chaudhury et al., 2003; Junier, 2000; Kristt et al., 1993; Kristt and Yarden, 1996; Tokita et al., 2001). Whether astrogliosis exerts a beneficial or detrimental effect on the lesion remains a matter of debate. On the one hand, reactive astrocytes are the most prevalent contributors to glial scars, which constitute a physical and chemical barrier to regeneration; on the other hand, reactive astrocytes also produce neurotrophic and neuroprotective factors and provide metabolic support. However, because ErbB signaling in astrocytes is involved in the uptake of extracellular glutamate and in the synthesis and release of various neurotrophic and neuroprotective factors, enhanced ErbB signaling in reactive astrocytes may provide a protective environment for the neurons. In a model of spinal cord injury, administration of TGFa promoted extensive axon growth. This was accompanied by increased astrocyte invasion and increased expression of laminin, which provides a substrate supportive to axon growth at the site of lesion (White et al., 2008). These results suggest that increased TGFa signaling may enhance the axonal growth-supportive action of astrocytes after spinal cord injury. Evidence suggesting that neuron-glia interactions, mediated through astrocytic ErbB signaling, are implicated in a pathological situation in the CNS has been obtained in the context of ischemic brain injuries. Using in vivo rat models of cerebral ischemia, intracerebral administration of TGFa significantly reduces the infarct volume, suggesting that stimulation of the TGFa-ErbB1 signaling pathway protects neurons from ischemic damage (Justicia et al., 2001; Justicia and Planas, 1999). Exploration of TGFa mode of action using in vitro models revealed that TGFa rescues neurons from NMDA-induced excitotoxicity, but only in the presence of astrocytes (Gabriel et al., 2003). TGFa exerts its neuroprotective action by stimulating the expression of PAI-1, an inhibitor of tissue-type plasminogen activator (t-PA), by astrocytes. PAI-1 inhibits the activity of t-PA, which is released by neurons and potentiates NMDA-induced excitotoxicity (Gabriel et al., 2003). In contrast to its neuroprotective action in the ischemic brain, activation of astrocytic ErbB signaling has been shown to be detrimental in other pathological situations. Glaucoma is an optic neuropathy, in which the optic nerve degenerates, usually in response to abnormally elevated intraocular pressure. Elevated hydrostatic pressure induces rapid phosphorylation of ErbB1 in astrocytes of the human optic nerve head in vitro. The pressuredependent activation of ErbB1 is necessary for inducible nitric oxide synthase (iNOS or NOS-2) induction and leads to excessive nitric oxide production, which is responsible for optic nerve axon

damage (Liu and Neufeld, 2003). The inhibition of ErbB1 signaling in astrocytes of the human optic nerve head may therefore be beneficial in the treatment or prevention of glaucoma. Thus, altered ErbB signaling in astrocytes may participate in many neurological disorders and may constitute a potential target for therapies. However, the question of whether stimulation or inhibition of this signaling system is required to obtain beneficial therapeutic effects will have to be evaluated for each pathological situation, since dysregulation of astrocytic ErbB signaling can exert opposite effects depending on the pathological context. 9. Conclusions and future perspectives Accumulating data has implicated astrocytic ErbB signaling in neuron-glia interactions. ErbB receptors expressed in astrocytes can sense many stimuli linked to neuronal activity and can couple neurotransmitter and neuromodulator inputs to ErbB-dependent downstream signaling pathways. However, much research is still needed to decipher the mechanisms and functional consequences of these neuron-to-glia communication processes involving astrocytic ErbB receptors. In vivo, individual astrocytes make contact with numerous neurons and synapses and integrate multiple neuronal stimuli. The ErbB signaling system has been described as a bow-tie-configured network, illustrating its capacity to sense diverse sources of stimuli and induce many distinct outputs through a conserved core of common signaling cascades (Citri and Yarden, 2006). Thus, the ErbB signaling network possesses all the properties enabling astrocytes to integrate many neuronal inputs and generate appropriate feedback signaling. The neuroendocrine control of reproduction in the hypothalamus provides an integrated example of how astrocytic ErbB receptor signaling coordinates neuron-to-astrocyte and astrocyte-to-neuron interactions governing a physiological function in the mature brain. In a broader context, these data raise the intriguing possibility that the orchestration of neuron-glia communication by astrocytic ErbB signaling mediates other fundamental physiological functions of the adult CNS that involve ErbB signaling, such as the response to stress (Burrows et al., 2000; Hilakivi-Clarke et al., 1993, 1992; Koshibu et al., 2005) and locomotor and feeding behaviors (Snodgrass-Belt et al., 2005). Moreover, the increasingly recognised role of astrocytes to the course of many neurological disorders, as well as the frequent dysregulation of erbB signaling in these pathological situations, suggest that exploration of the astrocytic erbB signaling may be interesting from a pathogenic and therapeutic perspective. The vast majority of data gathered on the role of astrocytic ErbB signaling in neuron-glia interactions have concerned ErbB1 receptor and its ligands. The predominant use of primary cultures of rodent cortical astrocytes, which only express ErbB1 and ErbB2, to investigate the effects of ErbB ligands in astrocytes may explain the paucity of data concerning the role of NRG signaling in astrocytes. Nonetheless, an extensive body of literature has implicated NRG1-ErbB signaling as a key component in the regulation of axon-Schwann cell interactions during development and in the adult peripheral nervous system (Chen et al., 2006; Corfas et al., 2004b). Our recent observation that human cortical astrocytes also express a functional NRG/ErbB3 signaling system (Sharif et al., 2009) opens a new field of investigation. Within the adult human cerebral cortex, astrocytes exhibit increased size, complexity and diversity compared to rodents, and such features may underlie an increased ability to integrate and process neuronal inputs (Oberheim et al., 2006). The addition of ErbB3 receptors to human cortical astrocytes during evolution may have contributed to the enhancement of the functional competency of neuron-glia communication by providing increased possibilities for extracellular stimuli sensing and intracellular pathway

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coupling. The exploration of the role of NRG-ErbB3 signaling in neuron-glia interactions may also have significance in the understanding of schizophrenia, since both astrocyte dysfunction and impairment of the NRG-ErbB signaling in the prefrontal cortex have been implicated in the pathogenesis of this disease (Corfas et al., 2004a). In total, a growing body of data has implicated astrocytic ErbB signaling in various key aspects of neuron-glia communication. Future studies will help to construct a unifying picture of the role of this signaling system in the pathophysiology of the mature CNS. Acknowledgements We thank Dr. Jean-Claude Beauvillain for his critical reading of this manuscript. This work was supported by Inserm Grants U816 and U837 (VP), the University of Lille 2 (VP), the Institut National du Cancer (INCa) (AS and VP), the Agence National pour la Recherche (ANR, France) (VP), the Re´gion Nord Pas de Calais and the Fondation pour la Recherche Me´dicale (FRM, France) (AS and VP). References Alexi, T., Hefti, F., 1993. Trophic actions of transforming growth factor alpha on mesencephalic dopaminergic neurons developing in culture. Neuroscience 55, 903–918. Apostolakis, E.M., Garai, J., Lohmann, J.E., Clark, J.H., O’Malley, B.W., 2000. Epidermal growth factor activates reproductive behavior independent of ovarian steroids in female rodents. Mol. Endocrinol. 14, 1086–1098. Araque, A., Carmignoto, G., Haydon, P.G., 2001. Dynamic signaling between astrocytes and neurons. Annu. Rev. Physiol. 63, 795–813. Araque, A., Li, N., Doyle, R.T., Haydon, P.G., 2000. SNARE protein-dependent glutamate release from astrocytes. J. Neurosci. 20, 666–673. Araujo, D.M., Cotman, C.W., 1992. Basic FGF in astroglial, microglial, and neuronal cultures: characterization of binding sites and modulation of release by lymphokines and trophic factors. J. Neurosci. 12, 1668–1678. Aronica, E., Gorter, J.A., Ijlst-Keizers, H., Rozemuller, A.J., Yankaya, B., Leenstra, S., Troost, D., 2003. Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins. Eur. J. Neurosci. 17, 2106–2118. Bains, J.S., Oliet, S.H., 2007. Glia: they make your memories stick! Trends Neurosci. 30, 417–424. Baroncini, M., Allet, C., Leroy, D., Beauvillain, J.C., Francke, J.P., Prevot, V., 2007. Morphological evidence for direct interaction between gonadotrophin-releasing hormone neurones and astroglial cells in the human hypothalamus. J. Neuroendocrinol. 19, 691–702. Bekar, L.K., He, W., Nedergaard, M., 2008. Locus coeruleus alpha-adrenergic-mediated activation of cortical astrocytes in vivo. Cereb. Cortex 18, 2789–2795. Belcheva, M.M., Tan, Y., Heaton, V.M., Clark, A.L., Coscia, C.J., 2003. Mu opioid transactivation and down-regulation of the epidermal growth factor receptor in astrocytes: implications for mitogen-activated protein kinase signaling. Mol. Pharmacol. 64, 1391–1401. Benzel, I., Bansal, A., Browning, B.L., Galwey, N.W., Maycox, P.R., McGinnis, R., Smart, D., St Clair, D., Yates, P., Purvis, I., 2007. Interactions among genes in the ErbBNeuregulin signalling network are associated with increased susceptibility to schizophrenia. Behav. Brain Funct. 3, 31. Bouret, S., De Seranno, S., Beauvillain, J.C., Prevot, V., 2004. Transforming growth factor beta1 may directly influence gonadotropin-releasing hormone gene expression in the rat hypothalamus. Endocrinology 145, 1794–1801. Bouvier-Labit, C., Chinot, O., Ochi, C., Gambarelli, D., Dufour, H., Figarella-Branger, D., 1998. Prognostic significance of Ki67, p53 and epidermal growth factor receptor immunostaining in human glioblastomas. Neuropathol. Appl. Neurobiol. 24, 381–388. Burrows, R.C., Levitt, P., Shors, T.J., 2000. Postnatal decrease in transforming growth factor alpha is associated with enlarged ventricles, deficient amygdaloid vasculature and performance deficits. Neuroscience 96, 825–836. Buxbaum, J.D., Georgieva, L., Young, J.J., Plescia, C., Kajiwara, Y., Jiang, Y., Moskvina, V., Norton, N., Peirce, T., Williams, H., Craddock, N.J., Carroll, L., Corfas, G., Davis, K.L., Owen, M.J., Harroch, S., Sakurai, T., O’Donovan, M.C., 2008. Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene. Mol. Psychiatry 13, 162–172. Casper, D., Mytilineou, C., Blum, M., 1991. EGF enhances the survival of dopamine neurons in rat embryonic mesencephalon primary cell culture. J. Neurosci. Res. 30, 372–381. Chaudhury, A.R., Gerecke, K.M., Wyss, J.M., Morgan, D.G., Gordon, M.N., Carroll, S.L., 2003. Neuregulin-1 and erbB4 immunoreactivity is associated with neuritic plaques in Alzheimer disease brain and in a transgenic model of Alzheimer disease. J. Neuropathol. Exp. Neurol. 62, 42–54.

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