| Proper synaptic growth and plasticity are critical for higher brain functions including memory and learning. We are interested in identifying and characterizing mechanisms that underlie the regulation of morphological and functional synaptic plasticity. To that end, we conducted a forward genetic gain-of-function screen aimed at identifying novel regulators of synaptic growth, using Drosophila larval neuromuscular junction (NMJ) as a model synapse. From this screen, we identified a well-conserved microRNA cluster, miR-310-313, whose expression affects synaptic plasticity at Drosophila NMJ. We generated a deletion of this miRNA cluster by imprecise excision of a P-element. Our results show that lack of miR-310-313 leads to a significant increase in evoked post-synaptic current and in quantal content, a measure of the efficiency of presynaptic neurotransmitter release. This phenotype can be rescued by overexpressing miR-310-313 during larval stage in nervous system, suggesting the temporal and tissue-specific requirement of this miR-310-313 cluster. miRNAs repress expression of their targets via base-pairing with the 3'UTR of their mRNAs. Computational algorithms predicted Khc-73, a member of Kinesin Superfamily proteins (KIFs), as one of the highest-scoring targets for miR-310-313. We hypothesize that miR-310-313 cluster regulates synaptic function by downregulating Khc-73. In support of our hypothesis, overexpressing Khc-73 in Drosophila motoneurons enhances synaptic function, a phenotype resembling miR-310-313 deletion. Further evidence shows that genetic removal of Khc-73, by using Khc-73 RNAi or by a deficiency uncovering Khc-73 genomic region, is sufficient to restore normal synaptic function in miR-310-313 deletion. Taken together, our data present a novel pathway by which synaptic plasticity is regulated. |
