Molecular basis of glutamatergic synapse function in inhibitory interneurons

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PROJECT SUMMARY Dysfunction of glutamatergic synapses in inhibitory interneurons (INs) is increasingly being linked to psychiatric diseases and neurological disorders. However, our understanding of the molecular mechanisms distinguishing glutamatergic synapse function in INs from those in excitatory neurons is hindered by a lack of insight into their molecular composition. The applicant's long-term goal is to develop an independent research career focusing on the molecular basis of glutamatergic synapse function in INs. The overall objective of this proposal is to identify IN-specific excitatory synaptic proteins (IN-ExSPs), and assess how these proteins regulate glutamatergic synapse function in INs. This proposal is aligned with the central hypothesis that unique protein specializations support the function of glutamatergic synapses in INs, at least in part, through the process of liquid-liquid phase separation (LLPS), a phenomenon that it ubiquitous across biology and has been recently linked to glutamatergic synapse function. The project's rationale is to establish a molecular framework for understanding how IN glutamatergic synapses impact health and disease. The central hypothesis will be tested by pursuing two specific aims: 1) Identify glutamatergic synaptic proteins specific to or enriched in interneurons; and 2) Evaluate the contribution of IN-ExSPs to glutamatergic synapse function in interneurons. Under the first aim, cell-type-specific immunoisolation and mass spectrometry will be used to identify novel IN-ExSPs. For the second aim, IN-ExSPs will be screened for LLPS-properties, and the effect of their overexpression or knockout on IN glutamatergic synapse function, and behaviour, will be assessed. The proposed research is innovative, in the applicant's opinion, firstly because it introduces a cell-type-specific dimension to the molecular-investigation of glutamatergic synapses; and secondly, because it assesses how IN-ExSPs that undergo LLPS influence glutamatergic synapse function in INs, which largely lack dendritic spines and therefore have a unique problem to overcome in terms of biochemical compartmentalization and synapse stability. The proposed research is significant because it will yield new insights into the molecular mechanisms supporting the function of glutamatergic synapses in INs, an area in which very little is currently known. This could uncover innovative strategies to selectively increase the function of glutamatergic synapses in INs, providing more precise therapeutic interventions to tackle psychiatric diseases and neurological disorders. The applicant has assembled an expert mentoring team to provide the technical training and career development guidance required to obtain a tenure track academic position. In particular, the applicant will receive training in electrophysiology and analysis of quantitative mass spectrometry data, and will further develop skills in molecular, biochemical, and advanced imaging techniques.