Grant: Canada Research Chairs

Synapses serve as information weigh stations between brain cells (neurons) where they coordinate the transmission of information from one neuron to the next. Understanding the mechanisms orchestrating synapse assembly and how these events impact a synapse’s ability to adapt to experience are central goals of the neurosciences. Heavily implicated in these processes are “synapse organizers” which serve as molecular codes that specify connectivity in a brain-region and cell type-selective fashion. The importance of synapse organizers is exemplified by the major brain disorders that emerge when their function is compromised, most notably, autism. Multiple cell types in the brain express a synapse organizer that powerfully suppresses synapse development, known as MDGAs, and compromising the function of these proteins triggers the onset of autism-like behaviors in mice. Accordingly, we are focused on deepening our understanding of their role in circuit assembly and function through our main Objectives: (1) study how MDGAs uniquely alter synapse development in different brain cells; (2) define how MDGAs coordinate synapse responses to ongoing neuronal activity; and (3) explore restorative effects of reversing molecular changes associated with loss of these suppressors. Approaches: Advancing our understanding of the ways MDGAs influence neural circuits requires exploring how these organizers regulate synapse properties, methods to probe circuit function, and behavioral assays. To accomplish this, we use a combination of genetic methods to access diverse cell types, physiological methods to measure circuit function, and behavioral assays to quantify restorative outcomes, using transgenic models of autism. Significance: By defining the developmental and plasticity landscapes of circuits harboring MDGAs, we will link susceptibility genes, synapse adaptation and circuit function, offering immense potential to generalize these relationships to neurodevelopmental disorders in humans. Insights gained into how MDGAs set the conditions for plasticity will expand the treatment options for diseases of the mind and brain, laying the foundation for approaches tailored specifically to the molecular and synaptic deficits we discover. Our neurotherapeutic strategies have the potential to enhance treatment efficacy while limiting side effects, reducing healthcare burden and costs and improving the lives of caregivers and those suffering with neurodevelopmental disorders.