GLUDINE

Proper brain function relies on a finely tuned balance between excitatory (EX) and inhibitory (IN) synaptic transmission, and disruptions in this balance are implicated in psychiatric and neurodevelopmental disorders. Understanding how this equilibrium is dynamically regulated during Hebbian synaptic plasticity is essential for identifying new therapeutic strategies. Neurexins (NRXNs) play a key role in regulating both EX and IN synapses by interacting with multiple postsynaptic partners, including Neuroligin1 (NLGN1) and cerebellin/delta glutamate receptor (GluD1) complexes. Recent findings suggest that NLGN1 and GluD1, which compete for NRXN binding, shape synaptic nanodomains and influence the distribution of AMPA, NMDA, and GABAA receptors. While previous research has focused primarily on their roles at EX synapses, emerging evidence indicates their presence at IN synapses as well. However, how NLGN1-GluD1 interactions contribute to synaptic organization and plasticity at both EX and IN synapses remains unknown. This proposal aims to unravel the molecular mechanisms underlying the NLGN1-GluD1 crosstalk and its impact on synaptic organization, plasticity, and cognition. We hypothesize that (1) the distribution and dynamics of NLGN1 and GluD1 are tightly linked at EX and IN synapses and (2) their functional interaction regulates the organization of glutamate and GABAA receptors, ultimately tuning synaptic plasticity and cognition. To address these questions, our multidisciplinary consortium will pursue a comprehensive 4-year research program focused on the CA1 region of the hippocampus. First, we will map the distribution and dynamics of NLGN1 and GluD1 across distinct hippocampal synapse types. Second, we will investigate the molecular determinants that govern their synapse-specific targeting, diffusion and accumulation. Finally, we will assess the impact of NLGN1-GluD1 crosstalk on synaptic organization, long-term plasticity, and cognitive function using advanced molecular and imaging techniques, including single-particle tracking, STORM super-resolution microscopy, and targeted protein immobilization strategies in vivo. By integrating molecular, electrophysiological, and imaging approaches, our project will provide novel insights into the shared and distinct roles of NLGN1 and GluD1 at EX and IN synapses. This work has the potential to redefine our understanding of synaptic plasticity mechanisms and inform new therapeutic strategies for disorders linked to excitatory/inhibitory imbalance.