Pathophysiological Mechanisms Of Neuregulin 1 Overexpression In GABAergic Interneurons

Although schizophrenia is a common and disabling genetic mental illness that affect 1% of the population worldwide.Cortical disinhibition is the main feature,often with unknown pathological mechanisms.Neuregulin-1(Nrg1)is schizophrenia susceptibility genes.In this study,we generated gtoNrg1 mice with overexpression of Nrg1 in GABAergic interneurons,which is used to study the pathophysiological mechanisms of cortical disinhibition in schizophrenia.In this study,we first analyzed Nrg1 gene expression in the post-mortem tissue of prefrontal cortex(PFC)from schizophrenia patients and healthy controls.Unexpectedly,Nrg1 expression was found to be specifically increased in GABAergic interneurons but not in pyramidal neurons from schizophrenia patients.Based on that,we generated gtoNrg1 mice in which Nrg1 overexpression specifically occurred in GABAergic interneurons and could be turned off by doxycycline(Dox).Through electrophysiological recording in brain slices and freely moving mice,we found that gtoNrg1 mice were disinhibited in the cellular,synaptic and neural network levels in the PFC.Then we conducted a series of behavioral test,gtoNrg1 mice showed hyperactive in the open-field test,PPI and social novelty deficits.The mechanistic study revealed the importance of interaction between NRG1 and Na_v1.1in regulating cortical disinhibition of gtoNrg1 mice.We further showed that chemogenetic activation of GABAergic interneurons in the PFC could rescue some behavioral deficits in gtoNrg1 mice such as hyperactive and social novelty deficits.Strikingly,both cortical disinhibition and behavioral deficits in gtoNrg1 mice can be reversed in adulthood by turning off Nrg1 overexpression.To sum up,we generated gtoNrg1 mice with overexpression of Nrg1 in GABAergic interneurons,and which had not been shown before.We have demonstrated the importance of NRG1 interacting with Na_v1.1 in regulating cortical disinhibition.Together,our results demonstrate mechanisms underlying cortical disinhibition related to schizophrenia and shed light on the pathophysiology of neuropsychiatric disorders.