Final Report Summary - NEUROMIR (microRNA function in homeostatic plasticity in the mammalian brain)
Using chronic pharmacological blockade of synaptic inhibition in hippocampal neurons as a model for synaptic downscaling, we identified a critical function for miR-134 in the downregulation of synaptic morphology and strength. This effect was mediated by inhibition of expression of the RBP Pumilio2, which in turn controls a pathway involved in AMPA-type glutamate receptor trafficking (Fiore et al., 2014). In follow-up studies, we performed a detailed analysis of the cellular mechanisms that control miR-134 function at both the neuron-wide and synaptic level in response to neuronal activity. First, we elucidated a dendritic transport mechanism dependent on the DEAH-box helicase DHX36 that is responsible for the dendritic localization of pre-miR-134 (Bicker et al., 2013). This suggests regulated pre-miR-134 local processing at synapses as one potential mechanism to increase miR-134 activity during scaling. Second, we discovered a coding-independent function of a dendritic RNA, Ube3a-1, in the regulation of local miR-134 activity (Valluy et al., 2015). Ube3a-1 works by sequestering miR379-410 microRNAs, thereby relieving repression of target mRNAs that are naturally repressed by these miRNAs upon association. Third, we characterized two RBPs that enhance miR-134 repressive activity via the regulation of the miRISC core component Argonaute (Störchel et al., 2015).
Finally, at the organismic level, we obtained evidence for a physiological role of miR379-410 microRNAs in rodent behavior.
In conclusion, results from this project significantly enhanced our understanding of the molecular mechanisms engaged during homeostatic plasticity in mammalian neurons, a process that is of vital importance for the experience-dependent development and function of neural circuits. Thus, our results form the basis for future studies that will test the potential of microRNA manipulation as novel therapeutic option for diseases that are charcterized by impaired neuronal homeostasis.