nNOS in Erbb4-positive neurons regulates GABAergic transmission in mouse hippocampus

Chaofan Wan, Yucen Xia, Jinglan Yan, Weipeng Lin, Lin Yao, Meng Zhang, Inna Gaisler-Salomon, Lin Mei, Dong Min Yin, Yongjun Chen

Research output: Contribution to journalArticlepeer-review


Neuronal nitric oxide synthase (nNOS, gene name Nos1) orchestrates the synthesis of nitric oxide (NO) within neurons, pivotal for diverse neural processes encompassing synaptic transmission, plasticity, neuronal excitability, learning, memory, and neurogenesis. Despite its significance, the precise regulation of nNOS activity across distinct neuronal types remains incompletely understood. Erb-b2 receptor tyrosine kinase 4 (ErbB4), selectively expressed in GABAergic interneurons and activated by its ligand neuregulin 1 (NRG1), modulates GABA release in the brain. Our investigation reveals the presence of nNOS in a subset of GABAergic interneurons expressing ErbB4. Notably, NRG1 activates nNOS via ErbB4 and its downstream phosphatidylinositol 3-kinase (PI3K), critical for NRG1-induced GABA release. Genetic removal of nNos from Erbb4-positive neurons impairs GABAergic transmission, partially rescued by the NO donor sodium nitroprusside (SNP). Intriguingly, the genetic deletion of nNos from Erbb4-positive neurons induces schizophrenia-relevant behavioral deficits, including hyperactivity, impaired sensorimotor gating, and deficient working memory and social interaction. These deficits are ameliorated by the atypical antipsychotic clozapine. This study underscores the role and regulation of nNOS within a specific subset of GABAergic interneurons, offering insights into the pathophysiological mechanisms of schizophrenia, given the association of Nrg1, Erbb4, Pi3k, and Nos1 genes with this mental disorder.

Original languageEnglish
Article number167
JournalCell Death and Disease
Issue number2
StatePublished - Feb 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research


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