miR-137 Regulation of Intrinsic Excitability

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Project Summary miRNAs are small, endogenous, non-coding RNAs that are increasingly being shown to play important roles in regulating gene expression. miR-137 is a highly conserved brain-enriched miRNA that has been linked to multiple brain disorders, including schizophrenia, autism spectrum disorder (ASD), bipolar disorder, and intellectual disability (ID). Our long-term goal is to identify all of the gene targets of miR-137 that affect intrinsic neuronal excitability, and understand how, when, and where these regulatory events contribute to signaling and plasticity in the nervous system. In the proposed studies, we will first examine how intrinsic and synaptic activity in neurons is changed in response to altered expression levels of miR-137, then identify the targets of miR-137 that contribute to altered excitability in vivo. Using Drosophila as an experimental system, we will combine powerful molecular-genetic tools, including CRISPR-Cas9 technology to make site-directed genomic changes, with biochemistry and electrophysiology to examine: 1) how intrinsic electrical activity in neurons is regulated by miR-137, and 2) if ion channel genes, including Kv4/Shal, Kv3/Shaw, KCNH/eag, Cav3/Ca-α1T, and Nav1/para ion channel genes, as well as other activity-related targets, are regulated by miR-137 to affect neuronal excitability in vivo.