Shoichet Lab │ Molecular Neurobiology and Genetics
Recent advances in human genetics indicate that neurodevelopmental disorders, in particular severe intellectual disability and autism, very often result from single gene defects. Interestingly, mutations in any single gene typically account for less than 1% of the patient population, but numerous genes, coding for proteins with diverse molecular functions, have been implicated in these monogenic forms. These genetic studies provide a useful starting point for identifying subgroups of proteins that are essential for normal neuronal network formation, and provide the basis for the focus of our research. Transmembrane receptors, cell adhesion molecules, and multiple scaffolding proteins at the postsynaptic density (PSD) have been implicated in both autism and intellectual disability, highlighting this structure as an obvious target for further analysis. We have shown that kinases capable of phosphorylating these PSD proteins are associated with related diseases, and it has recently become apparent that various post-translational modifications of both membrane-bound receptors and scaffolding proteins modulate synaptic transmission. We combine genetic and pharmacological approaches to explore these molecular events that potentially influence the formation and function of synapses and the generation of functional neuronal networks.