Grant: CIHR Fellowship

I am interested in how synaptic connections are formed in the brain. Synaptic development is coordinated by cell surface synapse organizing complexes. Mutations in several synaptic organizing proteins have been linked to autism and schizophrenia. Thus, it is important to understand how mutation of these genes alters brain development to increase disease risk. I propose to investigate the role of autism-linked MAM domain containing GPI anchor proteins (MDGA1 and MDGA2) in synapse development. It has been previously shown that MDGA1 prevents inhibitory synapse formation in cultured neurons by binding to neuroligin-2. My studies will test how MDGAs regulate synapse development in the mammalian brain and how their loss affects the balance between excitatory and inhibitory synaptic function. I will investigate MDGA1 and MDGA2 interactions with neuroligins using biochemical and fluorescence microscopy assays. I will investigate altered synaptic function in MDGA mutant animals using a combination of confocal and electron microscopy, and electrophysiology. I will also design interfering peptides that prevent MDGA1 biding to neuroligin-2, thus specifically upregulating inhibitory synapse formation and function. My proposed research links two gene families implicated in autism, MDGAs and neuroligins, into a single molecular pathway, and supports the idea that an imbalance between excitatory and inhibitory synaptic function contributes to this disorder.