Regulatory Elements Inserted Into Aavs Confer Preferential Activity In Cortical Interneurons

Cortical interneuron (CIN) dysfunction is thought to play a major role in neuropsychiatric conditions like epilepsy, schizophrenia and autism. It is therefore essential to understand how the development, phys ology and functions of CINs influence cortical circuit activity and behavior in model organisms such as miuo and pr ates. While transgen c driver lines are powerful tools for studying CINs in mice, this technology ia limited in other species. An alternative approach is to use viral vectors such as ARV, which can be used in mult ple species including primates and also have potential for therapeut c use in humans. Thus, we sought to discover gene regulatory enhancer elements (REs) that can be used in viral vectors to drive expression in specific cell types. The present study desc ibes the systematic genome-wide identification of putative REs (pREs) that are preferentially active in immature CINs by histone modification ChIP-seq. We evaluated two novel pREs in AAV vectors, alongside the well -established D/x 112b enhancer, and found that they drove CIN-specific reporter expression in adult mice. We also showed that the identified Ar14d pRE could drive sufficient expression of channelrhodopsin for optogenetic rescue of behavioral deficits in the D/x5/6+/- mouse model of fast-spiking CIN dysfunct