Neuregulin-1 Enhances Depolarization-Induced GABA Release

Woo, Ran-Sook; Li, Xiao Ming; Tao, Yanmei; Carpenter-Hyland, Ezekiel P.; Huang, Yang; Weber, Janet L.; Neiswender, Hannah; Dong, Xian‐Ping; Wu, Jiong; Gassmann, Martin; Lai, Cary; Xiong, Wen Cheng; Gao, Tian Ming; Mei, Lin

doi:10.1016/j.neuron.2007.04.009

Cited by 285 publications

(335 citation statements)

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“…We focused on the processing of Nrg1 and its receptor ErbB4 because the link between Nrg1, cognition, and the pathogenesis of schizophrenia has been made (12)(13)(14)(15). We cannot exclude the contribution of deficient processing of other substrates such as N-cadherin (data not shown) or amyloid precursor protein (6) to the phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…Nrg1 signaling via its receptor ErbB4 regulates NMDA receptor function of GABAergic interneurons in the PFC (10,12,13), and this regulation is perturbed in schizophrenic patients (14). Nrg1 signaling also regulates GABA release by these interneurons (15) and modifies their levels of ␣7 nicotinic acetyl choline receptors (16). How Nrg1 is mechanistically involved in the pathogenesis of schizophrenia remains unclear.…”

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confidence: 99%

“…Layer 5 of cerebral cortex and hippocampal CA1 consist of glutamatergic ''outflow'' neurons that connect to other brain areas such as ventral striatum. Disturbance of Nrg1 signaling in the context of schizophrenia pathogenesis is thought to occur primarily in these corticofugal neurons, which signal to ErbB4 receptors on inhibitory interneurons in the PFC and the hippocampus (15). Alleviated by Antipsychotic Drugs.…”

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confidence: 99%

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Deficiency of Aph1B/C-γ-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment

Dejaegere

Serneels

Schäfer

et al. 2008

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

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Regulated intramembrane proteolysis by ␥-secretase cleaves proteins in their transmembrane domain and is involved in important signaling pathways. At least four different ␥-secretase complexes have been identified, but little is known about their biological role and specificity. Previous work has demonstrated the involvement of the Aph1A-␥-secretase complex in Notch signaling, but no specific function could be assigned to Aph1B/C-␥-secretase. We demonstrate here that the Aph1B/C-␥-secretase complex is expressed in brain areas relevant to schizophrenia pathogenesis and that Aph1B/C deficiency causes pharmacological and behavioral abnormalities that can be reversed by antipsychotic drugs. At the molecular level we find accumulation of Nrg1 fragments in the brain of Aph1BC ؊/؊ mice. Our observations gain clinical relevance by the demonstration that a Val-to-Leu mutation in the Nrg1 transmembrane domain, associated with increased risk for schizophrenia, affects ␥-secretase cleavage of Nrg1. This finding suggests that dysregulation of intramembrane proteolysis of Nrg1 could increase risk for schizophrenia and related disorders.Alzheimer's ͉ knockout ͉ schizophrenia ͉ presenilin ͉ prepulse inhibition

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Deficiency of Aph1B/C-γ-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment

Dejaegere

Serneels

Schäfer

et al. 2008

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

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“…To this end, we used an ErbB4 inhibitor, AG1478, which prevents ErbB4 signaling 45,46 . We found that bath-applied AG1478 prevented NRG1β-mediated suppression of the Src enhancement of synaptic NMDAR currents (Fig.…”

Section: Nrg1β-erbb4 Blocks Src Enhancement Of Nmdar Epscs In Ca1mentioning

confidence: 99%

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

Pitcher

Kalia

et al. 2011

Nat Med

152

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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“…In agreement with this, NRG-1 has been shown to stimulate GABA release. 21 Interestingly, hypofunction of GABAergic interneurons, in particular of cells that express parvalbumin (PV), has been suggested to contribute to the etiology of schizophrenia. [22][23][24][25] Basket and chandelier cells that provide powerful perisomatic inhibition control and time the population firing of principal glutamatergic neurons, thereby coordinating network activity.…”

Section: Location Location Locationmentioning

confidence: 99%

Neuregulin links dopaminergic and glutamatergic neurotransmission to control hippocampal synaptic plasticity

Neddens

Vullhorst

Paredes

et al. 2009

Communicative & Integrative Biology

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Neuregulin-1 Enhances Depolarization-Induced GABA Release

Cited by 285 publications

References 51 publications

Deficiency of Aph1B/C-γ-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment

Deficiency of Aph1B/C-γ-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment

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

Neuregulin links dopaminergic and glutamatergic neurotransmission to control hippocampal synaptic plasticity

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