Grant: CIHR Fellowship

GPCRs represent a superfamily of proteins that facilitate cell-to-cell communications and participate in the regulation of all aspects of human physiology. GPCRs play a central role in human disease with 40% of prescribed pharmaceuticals having GPCRs as targets. Much of the effects of glutamate, the major neurotransmitter of cellular communications in the brain, are mediated by mGluRs: a subset of GPCRs that modulate learning, memory, and adaptability of the brain and have been increasingly implicated in neuropsychiatric disease. The striatum is a region of the brain at the nexus of both mGluR activity and neurological disease. It co-ordinates complex tasks including decision-making, reward, and motor control, and has been implicated in the pathology of depression, schizophrenia, ADHD, Parkinson's, and Huntington's disease. We recently discovered a family of cell-adhesion proteins (ELFN1 and ELFN2) that specifically interact with mGluRs on adjacent neurons. Mutations in ELFN1 have been associated with ADHD and epilepsy in humans and loss of ELFN1 in mice similarly results in hyperactivity, seizures, and abnormal response to psychostimulants suggesting the involvement of the striatum. Yet, virtually nothing is known about the mechanism of ELFN1/2 action in the striatum. We hypothesize ELFN1 and ELFN2 physically synchronize communications between neurons in the striatum. We will utilize precise genetic tools to remove ELFN1/2 from distinct neuronal populations in mice and perform behavioural evaluation to determine which disorders can be pinpointed to ELFN1 in the striatum. We will investigate the functional bias of ELFN1/2 action on mGluRs and dissect the possible mechanisms of disease-causing mutations in ELFN1. Finally, we will investigate the potential for a novel mechanism for synchronization of neuron-to-neuron communications by fully characterizing the assembly of ELFN1/2-containing protein complexes at cell junctions and their druggability for disease.