Myocyte Enhancer Factor 2c Regulates Dendritic Complexity and Connectivity of Cerebellar Purkinje Cells

Abstract

Mef2c haploinsufficiency is implicated in behavioral deficits related to autism, schizophrenia, and intellectual disability. Although perturbations in the cerebellum, notably Purkinje cells, have been linked to these neurological disorders, the underlying mechanisms remain poorly understood. In this study, we investigated the roles of Mef2c in cerebellar Purkinje cells during the first three weeks of postnatal development. Our analysis revealed that in comparison to other members of the Mef2 family, Mef2c expression is limited to postnatal Purkinje cells. Because the role of Mef2c has not been assessed in GABAergic neurons, we set out to determine the functional significance of Mef2c by knocking down the expression of Mef2c selectively in Purkinje cells. We found that the loss of Mef2c expression during the first and second postnatal week results in an increase in dendritic arborization without impact on the general growth and migration of Purkinje cells. The influence of Mef2c on dendritic arborization persists throughout the first three weeks, but is most prominent during the first postnatal week suggesting a critical period of Mef2c activity. Additionally, the loss of Mef2c expression results in an increase in the number of spines accompanied by an increase in Gad67 and vGluT1 puncta and decrease in vGluT2 puncta. Thus, our results reveal the specific expression and functional relevance of Mef2c in developing Purkinje cells and offer insight to how disruption of the expression of Mef2c in a GABAergic neuronal subtype may lead to pathogenesis of cerebellar-associated disorders.