Grant: Project Grant

About 1% of the Canadian population is affected by epilepsy. Although many mutations in genes involved in neuronal excitability have been identified as causative, other mutations in non-classical epilepsy genes have also been found. This is the case of mutations in a gene called DEPDC5 (DEP Domain Containing 5), a major genetic player involved in various diseases. Autistic features and psychiatric comorbidities are observed in patients with DEPDC5 mutations, thus suggesting an important role of this gene during brain development, but the exact mechanisms of DEPDC5-related pathogenesis are still unclear. More importantly, DEPDC5 mutations are usually associated with refractory epilepsies for which no treatment is currently available, thus strengthening the need to identify molecular clues of DEPDC5 pathogenicity. Our previous work described a zebrafish model of DEPDC5 loss-of-function that displays clinical features of epileptic patients. Importantly, we unveiled a previously unknown role of DEPDC5 and showed that it regulates the development of the inhibitory neuronal network in the brain. As a matter of fact, we provided the first in vivo evidence correlating DEPDC5 loss-of-function to neurodevelopmental defects that are likely to underlie epileptic and autistic pathogenicity. However, the underlying molecular mechanisms of DEPDC5 remain undiscovered. In this research plan, we hypothesize that a non-classical function of DEPDC5 is to regulate the expression of specific axon guidance genes (pcdhgs) necessary for developing inhibitory synaptic networks. Taking advantage of the genetic accessibility of the zebrafish embryo, we will test in vivo these genetic interactions when DEPDC5 is mutated. Altogether, our findings will unravel new non-classical function(s) of DEDPC5 and open new windows for developing therapies for untreated disorders caused by mutations in this gene.