Loss Of Foxg1 Impairs The Development Of Cortical SST-Interneurons Leading To Abnormal Emotional And Social Behaviors

FOXG1 syndrome is a severe encephalopathy that exhibit intellectual disability,emotional disorder and limited social communication.The emotional and cognitive symptoms of FOXG1 syndrome suggest that Foxg1 plays a potential role in the development of cortical interneurons.Previously,we demonstrated that the embryonic disruption of Foxg1 results in failed tangential migration,while postnatal deletion leads to abnormal distributions of interneurons in the cortex.Considering the emotional symptoms observed in FOXG1 syndrome and the link between SST-INs and neuropsychiatric disorders,here,an SST-Cre line was employed to specifically disrupt Foxg1 to investigate the cellular basis underlying the emotional clinical features of FOXG1 syndrome.Loss of Foxg1 resulted in an obvious reduction in the number of SST-INs,accompanied by an altered ratio of subtypes.Foxg1-deficient SST-INs exhibited decreased membrane excitability and a changed ratio of electrophysiological firing patterns,which subsequently led to an excitatory/inhibitory imbalance.Moreover,cognitive defects,limited social interactions,depression-like behaviors and elevated seizure susceptibility were detected in Foxg1 c KO mice.Treatment with low-dose of clonazepam effectively alleviated the defects.These results identify a link of SST-IN development to the aberrant emotion,cognition and social capacities in patients.Our findings identify a novel role of Foxg1 in SST-IN development and put new insights into the cellular basis of FOXG1 syndrome.