Overexpression of neuregulin 1 in GABAergic interneurons results in reversible cortical disinhibition

Yao-Yi Wang, Bing Zhao, Meng-Meng Wu, Xiao-Li Zheng, Longnian Lin and Dong-Min Yin ()
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Yao-Yi Wang: East China Normal University
Bing Zhao: East China Normal University
Meng-Meng Wu: East China Normal University
Xiao-Li Zheng: East China Normal University
Longnian Lin: East China Normal University
Dong-Min Yin: East China Normal University

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Cortical disinhibition is a common feature of several neuropsychiatric diseases such as schizophrenia, autism and intellectual disabilities. However, the underlying mechanisms are not fully understood. To mimic increased expression of Nrg1, a schizophrenia susceptibility gene in GABAergic interneurons from patients with schizophrenia, we generated gtoNrg1 mice with overexpression of Nrg1 in GABAergic interneurons. gtoNrg1 mice showed cortical disinhibition at the cellular, synaptic, neural network and behavioral levels. We revealed that the intracellular domain of NRG1 interacts with the cytoplasmic loop 1 of Nav1.1, a sodium channel critical for the excitability of GABAergic interneurons, and inhibits Nav currents. Intriguingly, activation of GABAergic interneurons or restoring NRG1 expression in adulthood could rescue the hyperactivity and impaired social novelty in gtoNrg1 mice. These results identify mechanisms underlying cortical disinhibition related to schizophrenia and raise the possibility that restoration of NRG1 signaling and GABAergic function is beneficial in certain neuropsychiatric disorders.

Date: 2021
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DOI: 10.1038/s41467-020-20552-y

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