PROJECT: JTC2015: SynPathy

Information processing in the brain critically depends on a balance between excitatory and inhibitory synaptic transmission (E/I balance), and E/I imbalances are observed in multiple neurodevelopmental disorders, including autism spectrum disorders (ASDs) and schizophrenia. While the molecular mechanisms by which neurons maintain stable E/I ratios and adjust them to activity changes are still unclear, synaptic adhesion proteins are thought to play a prominent role. However, it is entirely unknown how synaptic adhesion systems interact to recruit the synaptic machinery and set the E/I ratios of neurons. Our goal is to define key adhesion and scaffolding mechanisms that control E/I balance, with a particular focus on interacting gene products involved in ASDs and schizophrenia. We will characterize two families of synaptic surface proteins with validated genetic relevance for ASDs and schizophrenia: the MDGAs, a novel class of suppressors of synapse development, and the neuroligins (NLGNs), a family of synaptogenic adhesion proteins. By using genetic mouse models and patient-derived neurons, we will determine how the interplay between these synaptic surface proteins tunes E/I balance, how they recruit scaffolds and receptors, and how they signal to regulate local protein translation. We expect that our research strategy will define how corresponding genetic defects cause neurodevelopmental disorders, and provide important leads for novel diagnostic and therapeutic strategies.