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

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 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 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.

Automated summary

Increased expression of Nrg1 in GABAergic interneurons can cause cortical disinhibition, leading to various neuropsychiatric disorders. The interaction between NRG1 and Na(v)1.1 inhibits Na-v currents critical for GABAergic interneuron excitability, and activating GABAergic interneurons or restoring NRG1 expression can rescue related symptoms.