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Principal Investigator: Alexei Mansfield Bygrave
Organization: TUFTS UNIVERSITY BOSTON
Fiscal Year: 2024
Award: $241,578
Funding agency: National Institute of Mental Health
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.
Terms: <ANK Domain><ANK Repeat><Ammon Horn><Ankyrin Repeat><Ankyrin Repeat Domain><Area><Basic Research><Basic Science><Behavior><Binding Proteins><Biochemical><Biology><Brain><Brain Nervous System><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cellular Function><Cellular Physiology><Cellular Process><Complex><Connector Neuron><Cornu Ammonis><Coupled><DLG4><DLG4 gene><Data><Data Set><Dendritic Spines><Diffusion><Dimensions><Disease><Disorder><Dysfunction><Electrophysiology><Electrophysiology (science)><Encephalon><Functional disorder><Glutamates><Goals><Health><Hippocampus><Imaging Procedures><Imaging Technics><Imaging Techniques><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Intracellular Communication and Signaling><Investigation><Kinases><Knock-out><Knockout><Knowledge><L-Glutamate><Ligand Binding Protein><Ligand Binding Protein Gene><Link><Liquid substance><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mental disorders><Mental health disorders><Mentors><Mission><Molecular><NIH><National Institutes of Health><Nerve Cells><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neural Transmission><Neurocyte><Neurologic Disorders><Neurological Disorders><Neurons><Neurophysiology / Electrophysiology><Outcome><PSD95><Parvalbumins><Phase><Phosphatases><Phosphohydrolases><Phosphomonoesterases><Phosphoric Monoester Hydrolases><Phosphotransferase Gene><Phosphotransferases><Physiology><Physiopathology><Position><Positioning Attribute><Process><Property><Protein Binding><Proteins><Psychiatric Disease><Psychiatric Disorder><Public Health><Regulation><Research><Risk-associated variant><SAP90><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Subcellular Process><Synapses><Synaptic><Synaptic Transmission><Synaptic plasticity><Testing><Therapeutic Intervention><Training><Transphosphorylases><United States National Institutes of Health><biological signal transduction><bound protein><career><career development><cell type><dendrite spine><diffused><diffuses><diffusing><diffusions><electrophysiological><excitatory neuron><expectation><fluid><glutamatergic><hippocampal><improved><innovate><innovation><innovative><insight><intervention therapy><liquid><mental illness><neural circuit><neural circuitry><neurocircuitry><neurological disease><neuronal><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><overexpress><overexpression><pathophysiology><psychiatric illness><psychological disorder><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><scaffold><scaffolding><skills><synapse><synapse function><synaptic circuit><synaptic circuitry><synaptic function><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><tenure process><tenure track>