Mechanisms of Synapse Depression in Response to Postsynaptic Patterned Burst Firing



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Neuronal activity and experience stimulate synapse pruning (Zuo et al 2005b) to refine neuronal circuits during early postnatal development (Hua & Smith 2004), and are critical for learning and memory (Fu & Zuo 2011). Previous studies suggest that the activity-dependent transcription factor Myocyte Enhancer Factor 2 (MEF2) prunes functional and structural excitatory synapses in hippocampal and striatal neurons (Flavell et al 2006, Pulipparacharuvil et al 2008), findings that have been correlated with a role for MEF2 in behaviors, including memory formation (Barbosa et al 2008, Cole et al 2012, Dietrich 2013). Here, I report the use of a physiologically-relevant neuronal activity paradigm to study MEF2 transcriptional activity and function in the hippocampus. Utilizing optogenetics and biolistics, a method to sparsely express genes in neurons, I precisely controlled both activity and gene expression in a single neuron to study the cell-autonomous role of MEF2 in response to specific neuronal firing patterns. In my study, I demonstrate that postsynaptic burst firing, physiologically-relevant activity commonly observed in hippocampal CA1 pyramidal neurons, stimulates transcriptional activation of endogenous MEF2A and MEF2D transcription factors. I find that burst firing for 1 hr (which I refer to as 'brief' stimulation) elicits MEF2-dependent synapse depression. Although we hypothesized that the depression event was the result of synapse elimination, due to MEF2's known role as a negative regulator of excitatory synapse number (Flavell et al 2006, Pfeiffer et al 2010, Tsai et al 2012), surprisingly, we discovered that depression induced by brief stimulation was caused by silencing of synapses. Among potentially MEF2A/D-regulated genes, Arc was robustly induced by brief postsynaptic burst firing via activation of endogenous MEF2A/D. In contrast, chronic (24 hr) postsynaptic burst firing promotes an elimination of synapses that occurs independently of MEF2A/D. Overall, these results demonstrate the activation of MEF2 in response to physiological patterns of neural activity, and demonstrate that brief and chronic activity stimulate distinct mechanisms of synapse depression - MEF2-dependent synapse silencing, and MEF2-independent synapse elimination.

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