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

• Published in: Nature communications Vol. 12; no. 1; p. 278
• Main Authors: Wang, Yao-Yi, Zhao, Bing, Wu, Meng-Meng, Zheng, Xiao-Li, Lin, Longnian, Yin, Dong-Min
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 14/1; 38/88; 631/378/1689/1799; 631/378/340; 64/110; 82/83; 9/30; 9/74; Action Potentials; Animals; Autism; Behavior, Animal; Cellular communication; Dependovirus - metabolism; Disabilities; Excitability; gamma-Aminobutyric Acid - metabolism; Genotype; Humanities and Social Sciences; Hyperactivity; Intellectual disabilities; Interneurons; Interneurons - metabolism; Ion Channel Gating; Male; Mental disorders; Mice, Transgenic; multidisciplinary; Nerve Net - metabolism; Neural Inhibition; Neural networks; Neuregulin; Neuregulin 1; Neuregulin-1 - genetics; Neuregulin-1 - metabolism; Prefrontal Cortex - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Schizophrenia; Schizophrenia - genetics; Schizophrenia - physiopathology; Science; Science (multidisciplinary); Sodium; Sodium channels (voltage-gated); Sodium Channels - metabolism; γ-Aminobutyric acid
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20552-y

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 gto Nrg1 mice with overexpression of Nrg1 in GABAergic interneurons. gto Nrg1 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 Na v 1.1, a sodium channel critical for the excitability of GABAergic interneurons, and inhibits Na v currents. Intriguingly, activation of GABAergic interneurons or restoring NRG1 expression in adulthood could rescue the hyperactivity and impaired social novelty in gto Nrg1 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. The molecular and cellular mechanisms of cortical disinhibition as a common feature of many psychiatric diseases are not fully understood. The authors identify an interaction between NRG1 and Nav1.1 sodium channel as a mechanism of how NRG1 modulates the excitability of GABAergic interneurons.