Recent evidence suggests disruption of GABAergic inhibitory function as a likely mechanism underlying Autism Spectrum Disorders (ASD). In order to function correctly, neural networks must establish precise and stable interconnected circuits. Synaptic refinement mediated by GABAergic inhibitory neurons during development is necessary for the precision of brain function, and thus, developmental disruption of GABAergic inhibitory neurons (also known as interneurons) has the potential to perturb fundamental cortical functions, such as accurate encoding of sensory information and higher-order cognition. One major challenge in exploring GABAergic dysfunction is the diversity of inhibitory interneurons, which can be subdivided into distinct classes with different physiology, synaptic targets, and molecular markers. In the cortex, the largest interneuron class is comprised of fast-spiking basket cells that express parvalbumin (PV) and target the cell bodies of excitatory neurons, providing rapid, powerful inhibition. Dysregulation of PV-interneurons has been suggested as a candidate mechanism underlying autism, but little is known about the mechanistic contribution of PV- interneurons to ASD-related deficits. Selective disruption of PV-interneuron function in the context of ASD in will provide novel insight into specific GABAergic regulation and dysfunction in ASD. Genetic studies of ASD patients have identified Mef2c as a candidate gene. Small de novo deletions in the Mef2c locus, as well as missense mutations, have been reported in several unrelated patients with autistic features. Mef2c is an activity-dependent transcription that plays a role in synaptic function, and an haploinsufficiency mouse model of Mef2c result in behavioral phenotypes characteristic of ASD. The convergence of human studies, Mef2c function, and the ASD-like behaviors phenotypes present in the Mef2c haploinsufficiency mouse model makes Mef2c an excellent candidate gene for addressing the molecular, cellular and circuit dysfunctions underlying altered behavior in ASD. Mef2c is expressed in cortical excitatory neurons and PV-interneurons, however thus far the cell type-specific role of Mef2c for PV-interneuron function and its relation to ASDs remains unknown. Here, we will use combination of approaches that includes mouse genetics, behavior, histology, synaptic physiology, in vivo electrophysiology, and transcriptomic analyses to test the hypotheses that Mef2c signaling shapes PV-interneuron development, and that age-specific Mef2c-related disruptions of PV-interneurons will impair different aspects of synaptic transmission and cortical activity, gaining mechanistic insights into how impaired PV-interneuron dysfunction can contribute towards ASD symptoms.
Autism spectrum disorders (ASDs) are associated with cognitive deficits in perception, social interaction, and communication, and recent evidence suggests that the disruption of GABAergic inhibitory function is a likely mechanism underlying ASDs. One major challenge in exploring GABAergic dysfunction is the diversity of inhibitory interneurons, which can be subdivided into distinct classes with different physiology, synaptic targets, and molecular markers, and thus, will each have a unique contribution to ASD symptoms. This proposal will disrupt the expression of an ASD-linked gene in parvalbumin-expressing inhibitory interneurons to gain mechanistic insights into how impaired parvalbumin interneuron dysfunction can contribute toward ASD symptoms.
