MEF2C Hypofunction in GABAergic Cells Alters Sociability and Prefrontal Cortex Inhibitory Synaptic Transmission in a...

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• MEF2C haploinsufficiency syndrome (MCHS) is a neurodevelopmental disorder linked to heterozygous mutations or deletions in the MEF2C gene.
• MCHS is characterized by autism spectrum disorder and neurological symptoms, with MEF2C highly expressed in developing brain cells, including GABAergic neurons.
• The specific role of MEF2C hypofunction in GABAergic neurons regarding MCHS phenotypes remains largely unknown.

Purpose of the Study:

• To investigate the impact of MEF2C hypofunction specifically in GABAergic neurons on MCHS-like phenotypes in mice.
• To analyze the effects on behavior, gene expression, and prefrontal cortex microcircuit function.

Main Methods:

• Utilized GABAergic cell type-specific manipulations in mice to study Mef2c heterozygosity.
• Conducted behavioral tests, electroencephalography, single-cell transcriptomics, and patch-clamp electrophysiology with optogenetics.

Main Results:

• Mef2c heterozygosity in developing GABAergic cells led to female-specific deficits in social preference and altered approach-avoidance behavior.
• Observed differential gene expression in various cell types, including parvalbumin neurons, in females.
• Identified alterations in frontocortical network activity and reduced parvalbumin cell excitability and inhibitory transmission in females.

Conclusions:

• MEF2C hypofunction in developing GABAergic cells is crucial for typical sociability and prefrontal cortex inhibitory neuron function, particularly in females.
• Findings suggest that GABAergic cell-specific dysfunction in females with MCHS may contribute significantly to sociability symptoms, despite no apparent sex bias in human MCHS symptoms.