Title: Regulation of synapse development by the activity-regulated transcription factor MEF2
Description: In the nervous system, sensory experience is critical for both the proper maturation of synapses and the elimination of excess synapses within neural circuits that underlie behavior and cognition. Increased synaptic activity resulting from sensory experience leads to calcium influx into neurons, which activates signaling pathways that in turn activate transcription factors within the nucleus. Mutations in several genes that control activity-dependent transcription give rise to cognitive disorders in humans, suggesting that activity-dependent gene expression is essential for proper neural circuit development. However, it was not known how individual activity-regulated transcription factors coordinate aspects of synapse development required to generate mature neural circuits. We show that the neuronal activity-dependent activation of MEF2 family transcription factors restricts the number of excitatory synapses formed onto hippocampal neurons. In response to increased neuronal activity, calcium influx leads to the activation of the phosphatase calcineurin, which dephosphorylates and activates MEF2. The ability of MEF2 to restrict excitatory synapse number depends on its DNA binding activity as well as its regulation by calcineurin. These data indicate that in response to neuronal activity MEF2 activates a program of gene expression that regulates the number of excitatory synapses that neurons form and maintain.

To characterize the mechanisms by which MEF2 regulates synapse development, we perform a series of genome-wide analyses that identify the full complement of activity-regulated MEF2 target genes. The MEF2 targets identified in this context encode proteins with diverse functions at synapses, suggesting a broad role for MEF2 in synapse development and remodeling. Moreover, several MEF2 targets are mutated in human neurological disorders including epilepsy and autism-spectrum disorders. These analyses also reveal that neuronal activity leads to alternative polyadenylation site usage at many of the MEF2 target genes, resulting in the activity-dependent production of truncated mRNAs that may function to antagonize the activity of their full-length counterparts. Together, these experiments identify and characterize a MEF2-regulated program of gene expression that provides a link between neuronal activity and synapse development.