# Molecular basis of glutamatergic synapse function in inhibitory interneurons

> **NIH NIH R00** · TUFTS UNIVERSITY BOSTON · 2024 · $241,578

## Abstract

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 tec...

## Key facts

- **NIH application ID:** 10872127
- **Project number:** 5R00MH124920-05
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Alexei Mansfield Bygrave
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $241,578
- **Award type:** 5
- **Project period:** 2022-08-16 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872127

## Citation

> US National Institutes of Health, RePORTER application 10872127, Molecular basis of glutamatergic synapse function in inhibitory interneurons (5R00MH124920-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10872127. Licensed CC0.

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