Controlling of glutamate release by neuregulin3 via inhibiting the assembly of the SNARE complex

Ya Nan Wang, Dwight Figueiredo, Xiang Dong Sun, Zhao Qi Dong, Wen Bing Chen, Wan Peng Cui, Fang Liu, Hong Sheng Wang, Hai Wen Li, Heath Robinson, Er Kang Fei, Bing Xing Pan, Bao Ming Li, Wen Cheng Xiong, Lin Mei

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Neuregulin3 (NRG3) is a growth factor of the neuregulin (NRG) family and a risk gene of various severe mental illnesses including schizophrenia, bipolar disorders, and major depression. However, the physiological function of NRG3 remains poorly understood. Here we show that loss of Nrg3 in GFAP-Nrg3f/f mice increased glutamatergic transmission, but had no effect on GABAergic transmission. These phenotypes were observed in Nex-Nrg3f/f mice, where Nrg3 was specifically knocked out in pyramidal neurons, indicating that Nrg3 regulates glutamatergic transmission by a cell-autonomous mechanism. Consequently, in the absence of Nrg3 in pyramidal neurons, mutant mice displayed various behavioral deficits related to mental illnesses. We show that the Nrg3 mutation decreased paired-pulse facilitation, increased decay of NMDAR currents when treated with MK801, and increased minimal stimulation-elicited response, providing evidence that the Nrg3 mutation increases glutamate release probability. Notably, Nrg3 is a presynaptic protein that regulates the SNARE-complex assembly. Finally, increased Nrg3 levels, as observed in patients with severe mental illnesses, suppressed glutamatergic transmission. Together, these observations indicate that, unlike the prototype Nrg1, the effect of which is mediated by activating ErbB4 in interneurons, Nrg3 is critical in controlling glutamatergic transmission by regulating the SNARE complex at the presynaptic terminals, identifying a function of Nrg3 and revealing a pathophysiological mechanism for hypofunction of the glutamatergic pathway in Nrg3-related severe mental illnesses.

Original languageEnglish (US)
Pages (from-to)2508-2513
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number10
DOIs
Publication statusPublished - Mar 6 2018

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Keywords

  • Glutamatergic transmission
  • Nrg3
  • SNARE complex
  • Severe mental illness

ASJC Scopus subject areas

  • General

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