Date of Award

Summer 6-2-2023

Embargo Period

6-16-2028

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Christopher Cowan

Second Advisor

Lawrence Chandler

Third Advisor

Hainan Lang

Fourth Advisor

James Otis

Fifth Advisor

Catrina Robinson

Abstract

The MEF2 (Myocyte Enhancer Factor 2) family of transcription factors regulate gene expression controlling cell differentiation and synapse development. Loss-of-function mutations or deletions of the MEF2C gene cause a neurodevelopmental disorder, termed MEF2C Haploinsufficiency Syndrome (MCHS). MEF2C is highly expressed in excitatory forebrain neurons, microglia, and GABAergic neurons, but the effects of MEF2C hypofunction in GABAergic cells on MCHS-like phenotypes is not known. To study the role of MEF2C in GABAergic cell populations during mouse development, we generated mice that are GABAergic cell-specific Mef2c heterozygous mutants (Mef2cfl/+;Vgat-Cre or Mef2c cHetVgat). The Mef2c cHetVgat and littermate control mice underwent a battery of tests measuring MCHS-relevant phenotypes, including learning and memory, approach avoidance, and social preference. Mef2c cHetVgat mice exhibited altered spatial working memory. Interestingly, Mef2c cHetVgat female, but not male, mice displayed significant alterations in approach-avoidance and sociability. Using additional cell type-specific Cre driver lines, we found that MEF2C hypofunction in inhibitory neuron subtypes SST (somatostatin) and VIP (vasoactive intestinal peptide) populations alone cannot account for the behavioral phenotypes observed in Mef2c cHetVgat mice. Female Mef2c cHetVgat mice displayed social-related frontocortical network activity measured by electroencephalography. Using a single nucleus RNA-Seq approach, we found significant differentially expressed genes in PV-expressing cells with enrichment for risk genes linked to ASD, schizophrenia, and intellectual disability. Moreover, in female, but not male, mice, we observed that developmental, GABAergic-specific Mef2c heterozygosity produced significant alterations in excitatory/inhibitory balance and physiological properties of a GABAergic interneuron subtype, PV (parvalbumin) cells, in the prefrontal cortex (PFC), a brain region linked to social behavior deficits in multiple mouse models of ASD. Collectively, we find that MEFC hypofunction in female, but not male, developing GABAergic cells is important for sociability and approach-avoidance behaviors and PV inhibitory neuron function in the PFC of mice. While there is no apparent sex bias in ASD symptoms of MCHS, our new findings suggest that GABAergic cell-specific dysfunction in females with MCHS might contribute disproportionately to sociability symptoms.

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Copyright is held by the author. All rights reserved.

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Available for download on Friday, June 16, 2028

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