Characterization of Optimus Prime, A Novel Regulator Of Synaptic Transmission in Drosophila

Glutamate is the most abundant neurotransmitter in the human brain and is used for the fast transfer of information between neurons. Glutamate gated ion channels (aka ionotropic glutamate receptors) account for the largest majority of glutamatergic synapses. Given the prevalence of these synapses in the human brain, it’s not surprising that dysfunctional glutamate signaling manifests in many neurological disorders. Abnormalities can occur either pre or postsynaptically and are usually linked to gene mutations that impact glutamate release or postsynaptic responses. Here, I characterized a novel, highly conserved Drosophila protein named Optimus Prime (OPr) that was identified in a screen designed to find regulators of glutamatergic signaling. Interestingly, the OPr mammalian homolog, termed von Willebrand factor A domain-containing protein 8 (VWA8), has been linked to several neurological disorders, including autism, bipolar depression, and migraine. The neuromuscular junction (NMJ) of Drosophila third instar larvae was used as a model excitatory synapse to study the effects of loss of function mutants as well as OPr overexpression. In order to manipulate OPr expression levels genetic tools were generated to study the third instar larval NMJ. Using immunocytochemistry, we found that OPr localizes to presynaptic motor neurons at the NMJ. Consequently, loss of OPr affects larval locomotory behaviors, synaptic release, and NMJ morphology. In contrast, overexpression of OPr only affected NMJ morphology. These results suggest that OPr may function in two distinct pathways: 1) regulating neurotransmitter release, and 2) regulating synapse morphology. This work represents the first functional characterization of OPr in any species, and identifies OPr as novel regulator of glutamatergic synaptic function.