Activity-dependent regulation of Neu differentiation factor/neuregulin expression in rat brain

Eilam, Raya; Pinkas‐Kramarski, Ronit; Ratzkin, Barry; Segal, Menahem; Yarden, Yosef

doi:10.1073/pnas.95.4.1888

Cited by 96 publications

(74 citation statements)

References 51 publications

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“…36), indicating that a physiological role of NRG1-ErbB4 signaling is to suppress LTP at Schaffer collateral-CA1 synapses. The differential effect of NRG1-ErbB4 signaling on LTP induction but not on basal NMDAR currents is consistent with increasing neuronal activity causing NRG1 release in the hippocampus 60 . Alternatively, there might be tonic release of NRG1, which suppresses Src-enhanced but not basal NMDAR currents.…”

Section: Discussionmentioning

confidence: 53%

Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

Pitcher

Kalia

et al. 2011

Nat Med

153

146

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Hypofunction of the N-methyl D-aspartate subtype of glutamate receptor (NMDAR) is hypothesized to be a mechanism underlying cognitive dysfunction in individuals with schizophrenia. For the schizophrenia-linked genes NRG1 and ERBB4, NMDAR hypofunction is thus considered a key detrimental consequence of the excessive NRG1-ErbB4 signaling found in people with schizophrenia. However, we show here that neuregulin 1β-ErbB4 (NRG1β-ErbB4) signaling does not cause general hypofunction of NMDARs. Rather, we find that, in the hippocampus and prefrontal cortex, NRG1β-ErbB4 signaling suppresses the enhancement of synaptic NMDAR currents by the nonreceptor tyrosine kinase Src. NRG1β-ErbB4 signaling prevented induction of long-term potentiation at hippocampal Schaffer collateral-CA1 synapses and suppressed Src-dependent enhancement of NMDAR responses during theta-burst stimulation. Moreover, NRG1β-ErbB4 signaling prevented theta burst-induced phosphorylation of GluN2B by inhibiting Src kinase activity. We propose that NRG1-ErbB4 signaling participates in cognitive dysfunction in schizophrenia by aberrantly suppressing Src-mediated enhancement of synaptic NMDAR function.Correspondence should be addressed to M.W.S. (mike.salter@utoronto.ca). 5 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Medicine website. AUTHOR CONTRIBUTIONSG.M.P. designed the project, conducted the hippocampal experiments, analyzed the data and wrote the manuscript. L.V.K. and D.N. carried out and analyzed biochemical experiments. E.K.L. oversaw and analyzed the prefrontal cortex experiments. N.M.G. carried out and analyzed the prefrontal cortex experiments. K.T.Y. maintained, housed and provided ErbB4 knockout mice. All authors participated in revising the manuscript and agreed to the final version. M.W.S. conceived the study, analyzed data, supervised the overall project and wrote the manuscript. COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/. Nat Med. Author manuscript; available in PMC 2012 January 23. CIHR Author Manuscript CIHR Author Manuscript CIHR Author ManuscriptThe NMDAR, a major excitatory ligand-gated ion channel in the central nervous system and a principal mediator of synaptic plasticity, is a multiprotein complex whose core is a heterotetramer comprising two obligate GluN1 subunits and two GluN2(A-D) subunits 1,2 . Proteins associated with the core NMDAR have key roles in trafficking, stability, subunit composition and function of NMDARs 3 . A key process regulating NMDAR activity is phosphorylation by NMDAR-associated kinases. Certain NMDAR-dependent functions, such as ventilation and locomotion, may be independent of NMDAR phosphorylation 4 , whereas phosphorylation-induced upregulation of NMDARs is critical for synaptic plasticity [5][6][7] .A prominent hypothesis for the pathophysiology of schizophrenia is that core symptoms such as...

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Section: Discussionmentioning

confidence: 53%

Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

Pitcher

Kalia

et al. 2011

Nat Med

153

146

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“…Thus, the possibility that the reported increases in NRG1 or erbB4 expression (4,5,34,35) or erbB4 activation (36) reflect a compensatory response to a loss/reduction in function in this signaling pathway needs to be considered. This signaling pathway may also contribute to neuropsychiatric disorders through nongenetic mechanisms because both NRG1 and erbB4 expression have been shown to be altered by environmental insults (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders

Roy

Murtie

El-Khodor

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

294

238

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Several psychiatric disorders are associated with white matter defects, suggesting that oligodendrocyte (OL) abnormalities underlie some aspects of these diseases. Neuregulin 1 (NRG1) and its receptor, erbB4, are genetically linked with susceptibility to schizophrenia and bipolar disorder. In vitro studies suggest that NRG1-erbB signaling is important for OL development. To test whether erbB signaling contributes to psychiatric disorders by regulating the structure or function of OLs, we analyzed transgenic mice in which erbB signaling is blocked in OLs in vivo. Here we show that loss of erbB signaling leads to changes in OL number and morphology, reduced myelin thickness, and slower conduction velocity in CNS axons. Furthermore, these transgenic mice have increased levels of dopamine receptors and transporters and behavioral alterations consistent with neuropsychiatric disorders. These results indicate that defects in white matter can cause alterations in dopaminergic function and behavior relevant to neuropsychiatric disorders.dopamine ͉ erbB receptor ͉ neuregulin ͉ schizophrenia ͉ white matter N euregulin 1 (NRG1), a growth factor essential for brain development, and erbB4, one of its receptors, are genetically linked to schizophrenia and bipolar disorder (1-4). A role for NRG1-erbB receptor signaling in psychiatric diseases is also supported by studies showing that expression levels or function of NRG1, erbB3, and erbB4 are altered in patient tissues (1,4,5). Moreover, mice with reduced levels of NRG1 or erbB4 exhibit behavioral alterations relevant to mental illness (6-9). Although the evidence linking this pathway and psychiatric disorders is strong, the mechanisms by which it contributes to these diseases remain unknown. NRG1-erbB signaling is important in neurons, astrocytes, and oligodendrocytes (OLs), but the specific cell types through which altered NRG1-erbB signaling contributes to these disorders is undefined.Significant alterations in white matter are found in schizophrenia, bipolar disorder, major depression, anxiety, and obsessivecompulsive disorder (10-14), and genes expressed by OLs have been linked with some of these diseases (15, 16). Interestingly, NRG1-erbB signaling regulates OL development in vitro (17), although this has not been shown in the intact organism.To determine whether erbB signaling plays a role in CNS myelination and whether disruption of this pathway in OLs produces defects related to human psychiatric disorders, we analyzed mice in which erbB signaling in OLs is blocked by expression of a dominant negative erbB receptor (DN-erbB4) (18). We show that alterations in erbB signaling lead to changes in OL morphology, number, and function in vivo. Moreover, these transgenic (Tg) mice have increased levels of functional dopamine transporters (DAT) and D1 receptors and exhibit behavioral alterations suggestive of neuropsychiatric disorders. Together, these results indicate that altered NRG1-erbB signaling in OLs may be a potential contributor to the pathogenesis of mental illness....

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“…There is evidence to support the notion that NRG1 regulates long-term plasticity in the brain. 25,26,27 , so the increased neurotransmission that is induced by NRG1 and the subsequent production of more NRG1 are likely to contribute to long-term synaptic plasticity. …”

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confidence: 99%

Neuregulin 1 in neural development, synaptic plasticity and schizophrenia

2008

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Schizophrenia is a highly debilitating mental disorder that affects −1% of the general population, yet it continues to be poorly understood. Recent studies have identified variations in several genes that are associated with this disorder in diverse populations, including those that encode neuregulin 1 (NRG1) and its receptor ErbB4. The past few years have witnessed exciting progress in our knowledge of NRG1 and ErbB4 functions and the biological basis of the increased risk for schizophrenia that is potentially conferred by polymorphisms in the two genes. An improved understanding of the mechanisms by which altered function of NRG1 and ErbB4 contributes to schizophrenia might eventually lead to the development of more effective therapeutics.Schizophrenia is a severe and disabling mental disorder that is characterized by chronic positive symptoms (hallucinations, delusions and thought disorders), negative symptoms (social withdrawal, apathy and emotional blunting) and cognitive deficits. Although schizophrenia is a highly prevalent CNS disorder, it continues to be one of the least understood, primarily owing to its lack of pathological hallmarks. Most, if not all, commonly prescribed antipsychotics are anti-dopaminergic, and their use has been based on the 'classical' dopamine hypothesis, which posits that it is the hyperactivity of dopaminergic transmission that causes positive symptoms 1 . However, current antipsychotics are only modestly effective treatments for the cognitive dysfunction and negative symptoms that are associated with schizophrenia. Moreover, studies on the mechanism of action of antipsychotics have not been particularly informative about the pathogenesis of the disease 2 .Recent genetic studies have provided insight into the possible aetiological mechanisms of this devastating disorder. Schizophrenia has a significant genetic component, and several genes have been associated with the disorder in diverse populations 3 . In particular, the identification of polymorphisms in the genes that encode neuregulin 1 (NRG1) and its receptor ErbB4 has provided a useful starting point from which to better dissect the pathogenic mechanisms of schizophrenia. The past few years have witnessed major progress in our understanding of NRG1 function in neurodevelopment, neurotransmission and synaptic plasticity and of the potential pathological basis of the increased risk that is conferred by polymorphisms in NRG1 and ERBB4. In this Review we briefly discuss the basic signalling machinery of NRG1, review recent findings on the roles of NRG1 and ErbB signalling during development and synaptic plasticity, and explore the implications for the pathophysiology of schizophrenia.Correspondence to: Lin Mei, Email: E-mail: lmei@mcg.edu. NIH Public Access Author ManuscriptNat Rev Neurosci. Author manuscript; available in PMC 2009 May 14. Published in final edited form as:Nat Rev Neurosci. 2008 June ; 9(6): 437-452. doi:10.1038/nrn2392. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript NRG1 an...

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Activity-dependent regulation of Neu differentiation factor/neuregulin expression in rat brain

Cited by 96 publications

References 51 publications

Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders

Neuregulin 1 in neural development, synaptic plasticity and schizophrenia

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