Identification of novel functional and post-transcriptional regulatory mechanisms during homeostatic synaptic downscaling

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Neurons employ a nested set of homeostatic mechanisms to stabilize firing rates in the face of changes in network activity. Synaptic downscaling is one form of homeostatic plasticity where neurons weaken unitary synaptic strength in response to a chronic increase in network activity, in particular by decreasing synaptic expression of AMPA-type glutamate receptors (AMPA-R). Homeostatic synaptic downscaling is important both in activity-dependent neuronal development and in the etiology of neurological disorders, such as epilepsy. However, the molecular underpinnings of homeostatic synaptic downscaling are largely unknown. We have recently shown that the neuronal microRNA miR-134 is required for homeostatic synaptic downscaling in a rat hippocampal culture model by post-transcriptional control of the RNA-binding protein (RBP) Pumilio-2 (Fiore et al., 2014). Our preliminary results from quantitative proteomics suggest that the post-transcriptional downregulation of a plethora of synaptic genes, many of which are linked to postsynaptic calcium signaling and AMPA-R phosphorylation, is a hallmark of the neuronal response to increased network activity. Furthermore, we obtained preliminary evidence for a role of specific miRNAs and RBPs in the coordination of post-transcriptional inhibition of synaptic genes.In this proposal we plan to further elucidate the molecular mechanisms that regulate and execute homeostatic synaptic downscaling by1) Characterizing the function of newly identified genes regulated during homeostatic downscaling, focusing on the candidates Atp2b4 and Dcx and their interaction at the level of calcium signaling and AMPA-R trafficking and function. 2) Identifying the coordinated mechanisms underlying the post-transcriptional control of synaptic genes during downscaling, focusing on a crosstalk between the activity-regulated RNA-binding protein Rbfox1 and the microRNA miR-129-5p. The results from this project promise to provide significant new insight into the molecular mechanisms that execute and regulate homeostatic plasticity in response to chronic activation of neural networks, with important implications for activity-dependent neuronal development and neurological disorders characterized by impaired homeostatic plasticity, including epilepsy.