Micromanaging neuronal network: Regulatory control of neuronal wiring and plasticity by microRNAs.

Neurons, the computational unit of the brain, are wired to each other to form precise networks that regulate brain functions ranging from simple reflexes to complex behavior. The human brain has one hundred billion neurons and each neuron can form, on average, ten thousand connections or synapses. The fundamental problem in neuroscience is to understand how synaptic connections are made and how modifications of these synaptic connections (synaptic plasticity) occur in response to neuronal activity. More recently, much interest has focused on the post-transcriptional control of neuronal network formation, in particular by microRNAs (miRNAs) – a class of small non-coding RNAs that are emerging as key regulators of neuronal development and function. miRNAs guide a multi-protein complex, known as the RNA-induced silencing complex (RISC), to specific sites on mRNAs targeted for reversible silencing. However, molecular mechanism of miRNA-mediated spatio-temporal regulation of synaptic functions remains largely unknown. My study revealed that MOV10, a RISC protein, is rapidly degraded through the proteasome at the synapse upon synaptic activation. By setting a translation trap after RNAi-mediated loss of MOV10, I identified dendritic mRNAs whose synthesis at the synapse can be potentially modulated by activity dependent degradative control of the RISC. Among these mRNAs was Lysophospholipase 1 (Lypla1), a depalmitoylating enzyme that is repressed by miR-138. These findings elucidated a novel synaptic plasticity mechanism that involves combinatorial control of synaptic protein synthesis and degradation upon NMDA receptor activation.