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Synaptic dysfunction is implicated in a variety of neurological disorders. De novo mutations in certain synaptic proteins are pathogenic. In particular, rare variants of two NMDA receptor
subunits, GluN2A and GluN2B, underlie some cases of epilepsy and neurodevelopmental disorders.
For many years, my laboratory has worked on mechanisms regulating NMDA receptor trafficking to excitatory synapses and how synaptic localization is dynamically regulated during development and in response to experience. In particular, we have studied how the long C-terminal domains of GluN2A and GluN2B regulate trafficking through protein-protein interactions and posttranslational modifications such as phosphorylation. In particular we have evaluated a missense mutation within
the C-terminal domain of GluN2B identified in a patient with ASD and described deficits in receptor surface expression and dendritic spine density. We are moving forward to make a mouse model of this mutation. More recently we are studying a missense mutation located within the C-domain of GluN2A identified in a patient with epilepsy and intellectual disability. Thus residue is a phosphorylation site and affects receptor trafficking. Our studies validate a ‘bedside to bench’
approach of studying rare variants associated with disease to better understand the function and signaling properties of NMDA receptors. We anticipate our results will allow us to better understand the structure, function and signaling regulated by the C-termini. Importantly, by characterizing these variants, we hope to gain insight into the pathogenesis of various neurodevelopmental disorders.