Pre- and postsynaptic MEF2C promote experience-dependent, input-specific development of Layer 4 to Layer 2/3 excitatory synapses
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ABSTRACT:
PROVIDER: PRJNA1066371 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27638033_1.fastq.gz | Fastqsanger.gz | |||
| SRR27638033_2.fastq.gz | Fastqsanger.gz | |||
| SRR27638034_1.fastq.gz | Fastqsanger.gz | |||
| SRR27638034_2.fastq.gz | Fastqsanger.gz | |||
| SRR27638035_1.fastq.gz | Fastqsanger.gz |
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Project description:Experience and activity-dependent transcription is a candidate mechanism to mediate development and refinement of specific cortical circuits. Here we provide evidence that the activity-dependent transcription factor Myocyte-Enhancer Factor 2C (MEF2C) is required in both presynaptic layer 4 (L4) and postsynaptic L2/3 somatosensory (S1) cortical neurons for development of their synaptic connection. In contrast, synaptic inputs from local L2/3, contralateral S1, or ipsilateral frontal/motor cortex are unaffected by postsynaptic Mef2c deletion in L2/3 neurons. Postsynaptic MEF2C is required for L4 to L2/3 synapse function during, but not after, an early postnatal, experience-dependent period. Furthermore, homozygous and heterozygous Mef2c deletion in presynaptic L4 neurons weakens L4 to L2/3 excitatory synaptic inputs by decreasing presynaptic release probability. Our results suggested that experience or activity-dependent transcriptional activation of MEF2C promotes development of L4→L2/3 synapses. In support of this idea, expression of transcriptionally active MEF2C (MEF2C-VP16) rescued weak L4 to L2/3 synaptic strength in sensory deprived mice. Consistent with a presynaptic function for MEF2C, we find that MEF2C regulates the activity-dependent expression of many presynaptic assembly genes, including transsynaptic cell adhesion proteins and regulators of neurotransmitter release. This work provides mechanistic insight into the experience-dependent development of specific cortical circuits.
2025-01-17 | GSE253629 | GEO
Project description:Excitatory synapses occur mainly on dendritic spines, and spine density is usually correlated with the strength of excitatory synaptic transmission. We report that Nr4a1, an activity-inducible gene encoding a nuclear receptor, regulates the density and distribution of dendritic spines in CA1 pyramidal neurons. Nr4a1 overexpression resulted in elimination of the majority of spines; however, postsynaptic densities were preserved on dendritic shafts, and the strength of excitatory synaptic transmission was unaffected, showing that excitatory synapses can be dissociated from spines. mRNA expression profiling studies suggest that Nr4a1-mediated transcriptional regulation of the actin cytoskeleton contributes to this effect. Under conditions of chronically elevated activity, when Nr4a1 was induced, Nr4a1 knockdown increased the density of spines and PSDs specifically at the distal ends of dendrites. Thus, Nr4a1 is a key component of an activity-induced transcriptional program that regulates the density and distribution of spines and synapses. After 10 days in culture, dissociated mouse hippocampal neurons in 6-well plates were infected with lentivirus expressing either Flag-Nr4a1 or GFP and incubated for 6 days to allow for transgene expression. Total RNA was then isolated using RNeasy Plus kit (QIAGEN). Samples passing an mRNA quality check proceeded to quantitative analysis on Agilent-026655 4x44 Mouse Microarrays.
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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.
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Project description:Excitatory synapses occur mainly on dendritic spines, and spine density is usually correlated with the strength of excitatory synaptic transmission. We report that Nr4a1, an activity-inducible gene encoding a nuclear receptor, regulates the density and distribution of dendritic spines in CA1 pyramidal neurons. Nr4a1 overexpression resulted in elimination of the majority of spines; however, postsynaptic densities were preserved on dendritic shafts, and the strength of excitatory synaptic transmission was unaffected, showing that excitatory synapses can be dissociated from spines. mRNA expression profiling studies suggest that Nr4a1-mediated transcriptional regulation of the actin cytoskeleton contributes to this effect. Under conditions of chronically elevated activity, when Nr4a1 was induced, Nr4a1 knockdown increased the density of spines and PSDs specifically at the distal ends of dendrites. Thus, Nr4a1 is a key component of an activity-induced transcriptional program that regulates the density and distribution of spines and synapses.
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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.
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Project description:Enhanced synaptic wiring onto sparsely distributed memory engram cells supports contextual memory storage and recall, with negative-valence memories exhibiting greater salience. Protein-level adaptations of input-specific synaptic connectivity onto hippocampal CA1 engram cells, however, remains largely unexplored. By combining spatiotemporally restricted synapse labelling, sorting, and mass spectrometry, we generated a discovery-oriented proteomic dataset from samples enriched for CA1 engram cell synapses receiving CA3 input 72 h after neutral context exploration or aversive contextual fear conditioning. Differential analysis relative to an unlabelled comparator identified protein expression signatures associated with synapse structure, efficacy, and strength in CA1 engram cell synapses. Aversive learning induced predominantly postsynaptic protein expression patterns, whereas neutral context skewed towards presynaptic changes. This differential engram cell synapse proteome was enriched for genes linked to cognitive genetic traits and related disorders. Together, these data provide a first hypothesis-generating resource for investigations into the molecular basis of contextual memory at the level of the synapse.
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