Developmental Disruption of Mef2c in Medial Ganglionic Eminence–Derived Cortical Inhibitory Interneurons Impairs Cellular and Circuit Function

Abstract

BackgroundMEF2C is strongly linked to various neurodevelopmental disorders including autism, intellectual disability, schizophrenia, and attention-deficit/hyperactivity disorder. Mice that constitutively lack 1 copy of Mef2c or selectively lack both copies of Mef2c in cortical excitatory neurons display a variety of behavioral phenotypes associated with neurodevelopmental disorders. The MEF2C protein is a transcription factor necessary for cellular development and synaptic modulation of excitatory neurons. MEF2C is also expressed in a subset of cortical GABAergic (gamma-aminobutyric acidergic) inhibitory neurons, but its function in those cell types remains largely unknown. MethodsUsing conditional deletions of the Mef2c gene in mice, we investigated the role of MEF2C in parvalbumin-expressing interneurons (PV-INs), the largest subpopulation of cortical GABAergic cells, at 2 developmental time points. We performed slice electrophysiology, in vivo recordings, and behavior assays to test how embryonic and late postnatal loss of MEF2C from GABAergic INs impacts their survival and maturation and alters brain function and behavior. ResultsLoss of MEF2C from PV-INs during embryonic, but not late postnatal, development resulted in reduced PV-IN number and failure of PV-INs to molecularly and synaptically mature. In association with these deficits, early loss of MEF2C in GABAergic INs led to abnormal cortical network activity, hyperactive and stereotypic behavior, and impaired cognitive and social behavior. ConclusionsMEF2C expression is critical for the development of cortical GABAergic INs, particularly PV-INs. Embryonic loss of function of MEF2C mediates dysfunction of GABAergic INs, leading to altered in vivo patterns of cortical activity and behavioral phenotypes associated with neurodevelopmental disorders.