TheMef2cGene Dose-Dependently Controls Hippocampal Neurogenesis and the Expression of Autism-Like Behaviors

Abstract

Mutations in the activity-dependent transcription factorMEF2Chave been associated with several neuropsychiatric disorders. Among these, autism spectrum disorder (ASD)-related behavioral deficits are manifested. Multiple animal models that harbor mutations inMef2chave provided compelling evidence thatMef2cis indeed an ASD gene. However, studies in mice with germline or global brain knock-out ofMef2care limited in their ability to identify the precise neural substrates and cell types that are required for the expression ofMef2c-mediated ASD behaviors. Given the role of hippocampal neurogenesis in cognitive and social behaviors, in this study we aimed to investigate the role ofMef2cin the structure and function of newly generated dentate granule cells (DGCs) in the postnatal hippocampus and to determine whether disruptedMef2cfunction is responsible for manifesting ASD behaviors. Overexpression ofMef2c(Mef2cOE) arrested the transition of neurogenesis at progenitor stages, as indicated by sustained expression ofSox2+inMef2cOEDGCs.Conditional knock-out ofMef2c(Mef2ccko) allowed neuronal commitment ofMef2cckocells; however,Mef2cckoimpaired not only dendritic arborization and spine formation but also synaptic transmission ontoMef2cckoDGCs.Moreover, the abnormal structure and function ofMef2cckoDGCs led to deficits in social interaction and social novelty recognition, which are key characteristics of ASD behaviors. Thus, our study revealed a dose-dependent requirement ofMef2cin the control of distinct steps of neurogenesis, as well as a critical cell-autonomous function ofMef2cin newborn DGCs in the expression of proper social behavior in both sexes.