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MEF2C hypofunction in GABAergic cells alters neurotypical behavior and prefrontal cortex inhibitory synaptic transmission in a sex-dependent manner

ABSTRACT: MEF2C hypofunction in GABAergic cells alters neurotypical behavior and prefrontal cortex inhibitory synaptic transmission in a sex-dependent manner

PROVIDER: PRJNA962892 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24348007_1.fastq.gz	Fastqsanger.gz
	SRR24348007_2.fastq.gz	Fastqsanger.gz
	SRR24348008_1.fastq.gz	Fastqsanger.gz
	SRR24348008_2.fastq.gz	Fastqsanger.gz

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MEF2C hypofunction in GABAergic cells alters neurotypical behavior and prefrontal cortex inhibitory synaptic transmission in a sex-dependent manner

Project description:Heterozygous loss-of-function mutations or deletions of the MEF2C gene cause a neurodevelopmental disorder, termed MEF2C Haploinsufficiency syndrome (MCHS), that is characterized by autism spectrum disorder, intellectual disability, seizures, and other neurological symptoms. In mice, global Mef2c heterozygosity produces numerous behavioral phenotypes reminiscent of MCHS. MEF2C is highly expressed in multiple cell populations in the developing brain, including GABAergic inhibitory neurons. While MEF2C hypofunction in excitatory neurons or microglia alter neurotypical behaviors and brain circuit function, the impact of MEF2C heterozygosity in GABAergic neurons remains unknown.

2025-04-30 | GSE230873 | GEO

MEF2C Hypofunction in GABAergic Cells Alters Sociability and Prefrontal Cortex Inhibitory Synaptic Transmission in a Sex-Dependent Manner.

Project description:BackgroundHeterozygous mutations or deletions of MEF2C cause a neurodevelopmental disorder termed MEF2C haploinsufficiency syndrome (MCHS), characterized by autism spectrum disorder and neurological symptoms. In mice, global Mef2c heterozygosity has produced multiple MCHS-like phenotypes. MEF2C is highly expressed in multiple cell types of the developing brain, including GABAergic (gamma-aminobutyric acidergic) inhibitory neurons, but the influence of MEF2C hypofunction in GABAergic neurons on MCHS-like phenotypes remains unclear.MethodsWe employed GABAergic cell type-specific manipulations to study mouse Mef2c heterozygosity in a battery of MCHS-like behaviors. We also performed electroencephalography, single-cell transcriptomics, and patch-clamp electrophysiology and optogenetics to assess the impact of Mef2c haploinsufficiency on gene expression and prefrontal cortex microcircuits.ResultsMef2c heterozygosity in developing GABAergic cells produced female-specific deficits in social preference and altered approach-avoidance behavior. In female, but not male, mice, we observed that Mef2c heterozygosity in developing GABAergic cells produced 1) differentially expressed genes in multiple cell types, including parvalbumin-expressing GABAergic neurons, 2) baseline and social-related frontocortical network activity alterations, and 3) reductions in parvalbumin cell intrinsic excitability and inhibitory synaptic transmission onto deep-layer pyramidal neurons.ConclusionsMEF2C hypofunction in female, but not male, developing GABAergic cells is important for typical sociability and approach-avoidance behaviors and normal parvalbumin inhibitory neuron function in the prefrontal cortex of mice. While there is no apparent sex bias in autism spectrum disorder symptoms of MCHS, our findings suggest that GABAergic cell-specific dysfunction in females with MCHS may contribute disproportionately to sociability symptoms.

| S-EPMC10881314 | biostudies-literature

MEF2C hypofunction in neuronal and neuroimmune populations produces MEF2C haploinsufficiency syndrome behaviors in mice

Project description:MEF2C hypofunction in neuronal and neuroimmune populations produces MEF2C haploinsufficiency syndrome behaviors in mice

| PRJNA579584 | ENA

MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders

Project description:Numerous genetic variants associated with MEF2C are linked to autism, intellectual disability (ID) and schizophrenia (SCZ) – a heterogeneous collection of neurodevelopmental disorders with unclear pathophysiology. MEF2C is highly expressed in developing cortical excitatory neurons, but its role in their development remains unclear. We show here that conditional embryonic deletion of Mef2c in cortical and hippocampal excitatory neurons (Emx1-lineage) produces a dramatic reduction in cortical network activity in vivo, due in part to a dramatic increase in inhibitory and a decrease in excitatory synaptic transmission. In addition, we find that MEF2C regulates E/I synapse density predominantly as a cell-autonomous, transcriptional repressor. Analysis of differential gene expression in Mef2c mutant cortex identified a significant overlap with numerous synapse- and autism-linked genes, and the Mef2c mutant mice displayed numerous behaviors reminiscent of autism, ID and SCZ, suggesting that perturbing MEF2C function in neocortex can produce autistic- and ID-like behaviors in mice.

2016-09-23 | GSE87202 | GEO

Characterization of molecular changes associated with Mef2c hypofunction in the mouse auditory nerve

Project description:Characterization of molecular changes associated with Mef2c hypofunction in the mouse auditory nerve

| PRJNA758073 | ENA

MEF2C hypofunction in neuronal and neuroimmune populations produces MEF2C haploinsufficiency syndrome behaviors in mice

Project description:Microdeletions of the MEF2C gene are linked to a syndromic form of autism termed MEF2C haploinsufficiency syndrome (MCHS). Here, we show that MCHS-associated missense mutations cluster in the conserved DNA binding domain and disrupt MEF2C DNA binding. DNA binding-deficient global Mef2c heterozygous mice (Mef2c-Het) display numerous MCHS-like behaviors, including autism-related behaviors, as well as deficits in cortical excitatory synaptic transmission. We find that hundreds of genes are dysregulated in Mef2c-Het cortex, including significant enrichments of autism risk and excitatory neuron genes. In addition, we observe an enrichment of upregulated microglial genes, but not due to neuroinflammation in the Mef2c-Het cortex. Importantly, conditional Mef2c heterozygosity in forebrain excitatory neurons reproduces a subset of the Mef2c-Het phenotypes, while conditional Mef2c heterozygosity in microglia reproduces social deficits and repetitive behavior. Together our findings suggest that MEF2C regulates typical brain development and function through multiple cell types, including excitatory neuronal and neuroimmune populations.

2020-10-24 | GSE139419 | GEO

brpf1 knockdown reduces inhibitory neurotransmission and regulates gene expression of GABAergic interneurons derived from MGE

Project description:Our research is to investigate the role of Brpf1 in the development and function of GABAergic interneurons. To test this, we used mouse primary in vitro cultured GABAergic interneurons derived from medial ganglionic eminence (MGE) and utilized AAV-shBrpf1 virus to knockdown Brpf1. We performed mRNA-seq on the total RNA extracted from the infected neurons .We found that most of the up-regulated genes after Brpf1 knockdown were involved in processes such as protein binding, gene negative transcription, ubiquitination, and inflammation by mRNA-seq. We found that many genes related to neuronal calcium, potassium ion transport and neurotransmitter release changed after Brpf1 was knockdown.Our results demonstrate the key role of Brpf1 in related gene expression of GABAergic interneurons, and provide new lights on the underlying neurobiological mechanisms of BRPF1 mutations that cause mental retardation in children or adolescents.

2021-02-23 | GSE157903 | GEO

Early-life prefrontal cortex inhibition and early-life stress lead to long-lasting behavioral, transcriptional, and physiological impairments

Project description:Early-life stress has been linked to multiple neurodevelopmental and neuropsychiatric deficits. Our previous studies have linked maternal presence/absence from the nest in developing rat pups to changes in prefrontal cortex activity. Furthermore, we have shown that these changes are modulated by serotonergic signaling. Here we test whether changes in prefrontal cortex activity during early-life affect the developing cortex leading to behavioral alterations in the adult. We show that inhibiting the prefrontal cortex of mouse pups leads to cognitive deficits in the adult comparable to those seen following maternal separation. Moreover, we show that activating the prefrontal cortex during maternal separation can prevent these behavioral deficits. To test how maternal separation affects the transcriptional profile of the prefrontal cortex we performed single-nucleus RNA sequencing. Maternal separation lead to differential gene expression almost exclusively in inhibitory neurons. Among others, we found changes in GABAergic and serotonergic pathways in these interneurons. Interestingly, both maternal separation and early-life prefrontal cortex inhibition led to changes in physiological responses in prefrontal activity to GABAergic and serotonergic antagonists that were similar to the responses of more immature brains. Prefrontal activation during maternal separation prevented these changes. These data point to a crucial role of prefrontal cortex activity during early-life in behavioral expression in adulthood

2024-03-14 | GSE254342 | GEO

Transcriptome signatures of the medial prefrontal cortex underlying GABAergic control of resilience to chronic stress exposure

Project description:Transcriptome signatures of the medial prefrontal cortex underlying GABAergic control of resilience to chronic stress exposure

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MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia [mutant MEF2C]

Project description:In acute myeloid leukemia, chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that transgenic Mef2cS222A/S222A mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MLL-AF9. MEF2C phosphorylation was required for leukemia stem cell maintenance, induced by MARK kinases in cells, and blocked by selective MARK inhibitor MRT199665, which caused apoptosis of MEF2C-activated human AML cell lines and primary patient specimens, but not those lacking MEF2C. These findings identify signaling-dependent dysregulation of transcription factor control as a determinant of therapy response in AML, with immediate potential for improved diagnosis and therapy for this disease.

2018-07-23 | GSE94453 | GEO

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