Pre- and Postsynaptic MEF2C Promote Experience-Dependent, Input-Specific Development of Local Cortical Excitatory Synapses

Abstract

Complex and specific neocortical circuits mature postnatally through a combination of genetic factors and sensory experience-driven neural activity. Experience- and activity-dependent transcriptional factor activation is a candidate mechanism for the development and refinement of these circuits. Synapses form the basis of neurons. Robust synapse proliferation during development is closely followed by experience-dependent pruning and modification to preserve and strengthen circuits. Neurodevelopmental disorders, including Autism Spectrum Disorder, are characterized by synaptic and circuit properties that give rise to behavioral and cognitive deficits and symptoms. Transcription factor Myocyte Enhancer Factor 2 C (MEF2C) is highly expressed in the cortex during development and into adulthood and has been identified as a regulator of synaptic strength and transmission in a sensory experience-dependent manner. MEF2C has been shown to function in both repressive and activator roles in postsynaptic compartments; however, little is known about presynaptic regulation by MEF2C. Additionally, the mechanisms by which MEF2C regulates synapses in an activity- and input-specific manner are still largely unknown. My work provides evidence that the activity-dependent transcription factor MEF2C is required for experience-dependent development of inputs from Layer (L) 4 to L2/3 neurons in the mouse primary somatosensory barrel cortex (S1). Importantly, MEF2C is required in both presynaptic L4 and postsynaptic L2/3 neurons during the first two postnatal weeks for L4–L2/3 synapse development. MEF2C plays a local L4 input-specific role in postsynaptic L2/3 cells through the mechanism of reduced probability of presynaptic neurotransmitter release for L4 presynaptic MEF2C. Constitutively active MEF2C-VP16 can rescue the lack of whisker sensory input but does not rescue the loss of MEF2C in presynaptic neurons. Together, these results suggest that the activity-dependent transcriptional activation of MEF2C promotes the development of L4–L2/3 synapses. MEF2C is necessary for the activity-dependent expression of genes encoding pre-, post-, and transsynaptic proteins in cortical neurons. I examined the protein tyrosine kinase PYK2, which was found to be elevated in the cortex of MEF2C KO mice but appeared to be insufficient in affecting or regulating synaptic strength, like MEF2C. Altogether, this work provides insights into the mechanisms of MEF2C-mediatied, experience-dependent development of specific cortical circuits