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Pre- and postsynaptic MEF2C promote experience-dependent, input-specific development of Layer 4 to Layer 2/3 excitatory synapses

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE253629 | GEO | 2025/01/17

REPOSITORIES: GEO

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Project description:This is a model of one presynaptic and one postsynaptic cell, as described in the article: Gamma oscillation by synaptic inhibition in a hippocampal interneuronal network model. Wang XJ, Buzsáki G. J Neurosci. 1996 Oct 15;16(20):6402-13. PMID:8815919; Abstract: Fast neuronal oscillations (gamma, 20-80 Hz) have been observed in the neocortex and hippocampus during behavioral arousal. Using computer simulations, we investigated the hypothesis that such rhythmic activity can emerge in a random network of interconnected GABAergic fast-spiking interneurons. Specific conditions for the population synchronization, on properties of single cells and the circuit, were identified. These include the following: (1) that the amplitude of spike afterhyperpolarization be above the GABAA synaptic reversal potential; (2) that the ratio between the synaptic decay time constant and the oscillation period be sufficiently large; (3) that the effects of heterogeneities be modest because of a steep frequency-current relationship of fast-spiking neurons. Furthermore, using a population coherence measure, based on coincident firings of neural pairs, it is demonstrated that large-scale network synchronization requires a critical (minimal) average number of synaptic contacts per cell, which is not sensitive to the network size. By changing the GABAA synaptic maximal conductance, synaptic decay time constant, or the mean external excitatory drive to the network, the neuronal firing frequencies were gradually and monotonically varied. By contrast, the network synchronization was found to be high only within a frequency band coinciding with the gamma (20-80 Hz) range. We conclude that the GABAA synaptic transmission provides a suitable mechanism for synchronized gamma oscillations in a sparsely connected network of fast-spiking interneurons. In turn, the interneuronal network can presumably maintain subthreshold oscillations in principal cell populations and serve to synchronize discharges of spatially distributed neurons. The presynaptic and postsynaptic cell have identical parameters and the variables in each cell are identified by using _pre or _post as a postfix to their names. The presynaptic cell influences the postsynaptic one via the synapse (variables and parameters: I_syn, E_syn, g_syn, F, theta_syn, alpha, beta). The applied current to the presynaptic cell, I_app_pre, is set to 2 microA/cm2 for 10 ms as in figure 1C of the article. The dependence of the postsynaptic cell on directly applied current can be investigated in isolation by setting I_app_pre to 0 and altering I_app_post. Originally created by libAntimony v1.4 (using libSBML 3.4.1)

Project description:Background Local translation at synapses is important for rapidly remodeling the synaptic proteome to sustain long-term plasticity and memory. While the regulatory mechanisms underlying memory-associated local translation have been widely elucidated in the postsynaptic/dendritic region, there is no direct evidence for which RNA-binding protein (RBP) in axons controls target-specific mRNA translation to promote long-term potentiation (LTP) and memory. We previously reported that translation controlled by cytoplasmic polyadenylation element binding protein 2 (CPEB2) is important for postsynaptic plasticity and memory. Here, we investigated whether CPEB2 regulates axonal translation to support presynaptic plasticity. Methods Behavioral and electrophysiological assessments were conducted in mice with pan neuron/glia- or AQ2glutamatergic neuron-specific knockout of CPEB2. Hippocampal Schaffer collateral (SC)-CA1 and temporoammonic (TA)-CA1 pathways were electro-recorded to monitor synaptic transmission and LTP evoked by 4 trains of high-frequency stimulation. RNA immunoprecipitation, coupled with bioinformatics analysis, were used to unveil CPEB2-binding axonal RNA candidates associated with learning, which were further validated by Western blotting and luciferase reporter assays. Adeno-associated viruses expressing Cre recombinase were stereotaxically delivered to the pre- or post-synaptic region of the TA circuit to ablate Cpeb2 for further electrophysiological investigation. Biochemically isolated synaptosomes and axotomized neurons cultured on a microfluidic platform were applied to measure axonal protein synthesis and FM4-64FX-loaded synaptic vesicles. Results Electrophysiological analysis of hippocampal CA1 neurons detected abnormal excitability and vesicle release probability in CPEB2-depleted SC and TA afferents, so we cross-compared the CPEB2-immunoprecipitated transcriptome with a learning-induced axonal translatome in the adult cortex to identify axonal targets possibly regulated by CPEB2. We validated that Slc17a6, encoding vesicular glutamate transporter 2 (VGLUT2), is translationally upregulated by CPEB2. Conditional knockout of CPEB2 in VGLUT2-expressing glutamatergic neurons impaired consolidation of hippocampus-dependent memory in mice. Presynaptic-specific ablation of Cpeb2 in VGLUT2-dominated TA afferents was sufficient to attenuate protein synthesis-dependent LTP. Moreover, blocking activity-induced axonal Slc17a6 translation by CPEB2 deficiency or cycloheximide diminished the releasable pool of VGLUT2-containing synaptic vesicles. Conclusions We identified 272 CPEB2-binding transcripts with altered axonal translation post-learning and established a causal link between CPEB2-driven axonal synthesis of VGLUT2 and presynaptic translation-dependent LTP. These findings extend our understanding of memory-related translational control mechanisms in the presynaptic compartment.

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Pre- and postsynaptic MEF2C promote experience-dependent, input-specific development of Layer 4 to Layer 2/3 excitatory synapses

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