Pre- and postsynaptic MEF2C promote experience-dependent, input-specific development of cortical Layer 4 to Layer 2/3 excitatory synapses and regulate activity-dependent expression of synaptic cell adhesion molecules.

ABSTRACT

Experience and activity-dependent transcription is a candidate mechanism to mediate development and refinement of specific cortical circuits. Here we demonstrate that the activity-dependent transcription factor Myocyte-Enhancer Factor 2C (MEF2C) is required in both presynaptic layer 4 (L4) and postsynaptic L2/3 mouse (male and female) somatosensory (S1) cortical neurons for development of this specific synaptic connection. While postsynaptic deletion of Mef2c weakens L4 synaptic inputs, it has no effect on inputs from local L2/3, contralateral S1, or ipsilateral frontal/motor cortex. Similarly, homozygous, or heterozygous deletion of Mef2c in presynaptic L4 neurons weakens L4 to L2/3 excitatory synaptic inputs by decreasing presynaptic release probability. Postsynaptic MEF2C is specifically required during an early postnatal, experience-dependent, period for L4 to L2/3 synapse function and expression of transcriptionally active MEF2C (MEF2C-VP16) rescues weak L4 to L2/3 synaptic strength in sensory deprived mice. Together these results suggest that experience and/or activity-dependent transcriptional activation of MEF2C promotes development of L4 to L2/3 synapses. MEF2C regulated expression of many pre- and postsynaptic genes in postnatal cortical neurons. Interestingly, MEF2C was necessary for activity-dependent expression of many presynaptic genes, including those that function in transsynaptic adhesion and neurotransmitter release. This work provides mechanistic insight into the experience-dependent development of specific cortical circuits.Significance Statement Experience-driven neuronal activity is necessary for the development of synaptic connectivity of specific cortical circuits. Here we demonstrate that the activity-dependent transcription factor MEF2C is necessary for development of a specific synaptic connection between Layer (L)4 and L2/3 neurons in mouse somatosensory cortex. MEF2C is required in both presynaptic L4 and postsynaptic L2/3 neurons during an early postnatal and experience-dependent period for development of their connection. Our results suggest that sensory experience drives transcriptional activation of MEF2C to promote development of the L4 to L2/3 synaptic connection. We identify activity-dependent, MEF2C- regulated presynaptic genes that promote development of specific connections. This work provides insight into the mechanisms by which sensory experience determines development of cortical circuit connectivity.