411 Essential role for the neurodevelopmental disorder-linked gene, MEF2C, in inhibitory neuron function and neurotypical behaviors

Abstract

OBJECTIVES/GOALS: The MEF2 family of transcription factors regulate gene expression controlling cell differentiation and synapse development. Mutations or deletions in the MEF2C gene cause a neurodevelopmental disorder that includes symptoms of autism spectrum disorder. In this study, we aim to study the role of MEF2C in GABAergic populations using an animal model. METHODS/STUDY POPULATION: MEF2C Haploinsufficiency Syndrome (MCHS) occurs when there is one functional allele and one disrupted allele of MEF2C. To study the role of MEF2C in GABAergic populations during mouse development, we bred Vgat (vesicular GABA transporter)-Cre mice, which express cre recombinase broadly in early developing GABAergic neurons, with a floxed Mef2c loss-of-function mouse to create offspring that are GABAergic cell-specific Mef2c heterozygous mutants (Mef2c cHetVgat-cre). We then subjected these mutants and littermate controls to a battery of tests measuring MCHS-relevant phenotypes, including spatial working memory, anxiety-like behavior, social preference, sensory sensitivity, and Pavlovian learning and memory. RESULTS/ANTICIPATED RESULTS: Mef2c cHetVgat-cre mice showed significant deficits in spatial working memory, social preference, and contextual fear memory, all of which are prefrontal cortex (PFC)-dependent behaviors. Interestingly, we noted that conditional Mef2c knockout mice (Mef2c cKOVgat-cre) showed embryonic and early postnatal lethality, probable seizures, and severe motor coordination problems, highlighting the importance of MEF2C function in GABAergic populations. DISCUSSION/SIGNIFICANCE: We hypothesize that MEF2C plays a cell-autonomous role in GABAergic cells to control the balance of excitatory and inhibitory synaptic transmission in the developing and mature brain, which in the Mef2c cHet mice might be critical for PFC-dependent learning and memory and sociability.