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.
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Project description:The postsynaptic density (PSD) of excitatory synapses contains a highly organized protein network with thousands of proteins and is key node in the regulation of synaptic plasticity. To gain new mechanistic insight into experience-induced changes in the PSD, we examined the global dynamics of the hippocampal PSD proteome and phosphoproteome in mice following 4 different types of experience. Mice were trained using an inhibitory avoidance (IA) task and hippocampal PSD fractions were isolated from individual mice to investigate molecular mechanisms underlying experience-dependent remodeling of synapses. We developed a new strategy to identify and quantify the relatively low level of site-specific phosphorylation of PSD proteome from the hippocampus, by using a modified iTRAQ-based TiSH protocol. In the PSD, we identified 3,938 proteins and 2,761 phosphoproteins in the sequential strategy covering a total of 4,968 unique protein groups (at least 2 peptides including an unique peptide). On the phosphoproteins, we identified a total of 6,188 unambiguous phosphosites (75% site localization probability)
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Project description:Experience powerfully influences neuronal function and cognitive performance, but the cellular and molecular events underlying the experience-dependent enhancement of mental ability have remained elusive. In particular, the mechanisms that couple the external environment to the genomic changes underpinning this improvement are unknown. To address this we have used male mice harbouring an inactivating mutation of mitogen- and stress-activated protein kinase 1 (MSK1), a BDNF-activated enzyme downstream of the MAPK pathway. We show that MSK1 is required for the full extent of experience-induced improvement of spatial memory, for the expansion of the dynamic range of synapses, exemplified by the enhancement of hippocampal LTP and LTD, and for the regulation of the majority of genes influenced by enrichment. In addition, and unexpectedly, we show that experience is associated with an MSK1-dependent downregulation of key MAPK and plasticity-related genes, notably of EGR1/Zif268 and Arc/Arg3.1, suggesting the establishment of a novel genomic landscape adapted to experience. By coupling experience to homeostatic changes in gene expression MSK1, represents a prime mechanism through which the external environment has an enduring influence on gene expression, synaptic function and cognition.
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