The Role of MEF2 Transcription Factors in Neocortical Circuit and Synapse Development In Vivo




Rajkovich, Kacey Elise

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Proper neocortical circuit development requires postnatal experience and transcription. Neocortical neurons migrate to their proper layers and then undergo robust synapse proliferation to maximize contacts with presynaptic partners. Synapses are dynamic structures subjected to an equilibrium of formation and elimination rates to preserve meaningful and prune superfluous synapses, respectively. A neuron receives heterogeneous inputs and must tightly regulate connectivity with distinct presynaptic entities. Dysregulated connectivity causes aberrant circuit function and ultimately abnormal behavior linked with neurodevelopmental disorders such as autism. Therefore, a neuron must contain cellular machinery to regulate synaptic connectivity. The activity-dependent Myocyte Enhancer Factor-2 (MEF2) transcription factors - MEF2A-D - have distinct but overlapping expression profiles throughout the brain and typically suppress synapse number. The cell-autonomous role for specific MEF2 genes in neocortical circuit development has never been explored. Furthermore, a link between MEF2 and experience has never been identified within the neocortex. Lastly, whether MEF2 transcription factors regulate specific synaptic pathways is unknown.
I report that MEF2A, MEF2C, and MEF2D non-redundantly regulate synapse development onto individual pyramidal neurons within layers 2 and 3 (L2/3) of the postnatal mouse primary somatosensory "barrel" cortex in vivo. Simultaneous deletion of Mef2a and Mef2d modestly decreases spontaneous glutamatergic synaptic transmission in comparison to neighboring control L2/3 neurons. MEF2C, however, cell-autonomously mediates several unique aspects of L2/3 circuit development at a postsynaptic locus. Sparse Mef2c deletion decreases excitatory synapse number onto basal dendrites of L2/3 neurons targeted by local inputs. Therefore, Mef2c promotes excitatory synapse formation and/or maintenance in neocortex. Additionally, MEF2C and sensory experience interact to promote strength of local L2/3 inputs. Mef2c deletion depresses these local inputs in spared barrel cortices comparably to the depression induced by sensory deprivation via whisker trimming onto wildtype (WT) L2/3 neurons; hence MEF2C is required for experience-dependent development of L2/3 circuitry. Lastly, MEF2C differentially suppresses long-range intercortical while promoting connectivity at local L2/3 synaptic input pathways. These data represent novel mechanisms through which MEF2C regulates neocortical synapse development in vivo and provides insight into how activity-dependent transcription within the nucleus interacts with experience to alter specific synapse populations at the neural plasma membrane.

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