Grant: Project Grant

Our research is proposal is centered on investigating and targeting intracellular signaling pathways that are associated with seizures in people with epilepsy and autism spectrum disorders. Our project is founded on emerging evidence that amino acid metabolites are not simply passive "building blocks" of cellular components, but they also have important biochemical functions that impact brain activities by affecting specific intracellular communication pathways. Recently, genetic sequencing studies have identified pathological mutations in an important and evolutionarily-conserved amino acid signaling complex called GATOR1 in ~11% of familial forms of epilepsy, autism spectrum disorders, as well as in people who have died from SUDEP (sudden unexpected death in epilepsy). Within the French-Canadian population, GATOR1 mutations occur in ~5% of people with epilepsy. While it is not clear how GATOR1 defects effect the brain at a molecular level, the majority of people with defects in GATOR1-dependent amino acid signaling pathway are unable to control seizures with classical anti-epileptic drugs. Our hypothesis is that neuronal amino acid levels or genetic predispositions in the GATOR1 signaling pathway contribute to these neurological disorders by altering cellular protein expression and ability of neurons to properly communicate by altering synaptic development. This project aims to determine: 1) how GATOR1-dependent amino acid signaling contribute to the neuronal hyperexcitability, 2) how amino acid-signaling mechanisms are critical for regulating synaptogenesis, and 3) advance a novel inhibitory strategy of the pathway, developed by my lab, which shows promising effects to block seizures and prolong life in our genetically modified GATOR1-defective models.