# Nanoscale organization of the inhibitory synapse during synaptic plasticity

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2022 · $383,700

## Abstract

The correct balance between excitation and inhibition (E/I balance) in neuronal circuits is essential for learning
and memory, cognition and behavior. Disrupted inhibition leading to elevated neuronal and circuit excitability is
thought to underlie the pathology of numerous neurological disorders, therefore a comprehensive
understanding of the molecular mechanisms involved in synaptic inhibition will have the potential to direct new
therapeutic strategies for treating these conditions. GABAergic inhibitory synapses mediate the majority of
synaptic inhibition in the central nervous system, and their plasticity controls neuronal excitability and function.
The number of GABAA receptors (GABAARs) at inhibitory postsynaptic sites is a key determinant of inhibitory
synapse strength and hence neuronal inhibition. Therefore defining mechanisms by which synaptic GABAARs
are clustered and how they are altered in synaptic plasticity is imperative for understanding inhibition and its
disruption in brain disorders. Using the versatile super-resolution imaging technique, Structured Illumination
Microscopy (SIM), we find that GABAARs and their scaffold, gephyrin, form nanoscale subsynaptic domains
(SSDs) in the inhibitory postsynaptic domain, are modulated during plasticity, and form closely associated pairs
with presynaptic release SSDs in the active zone, suggesting that a modular nanoscale architecture for the
inhibitory synapse may be important for their plasticity and function. Our goal is to determine the mechanisms
that control inhibitory nanoscale organization, understand how this organization influences inhibitory synaptic
function and is altered during synaptic plasticity, and determine how these facets differ between diverse
inhibitory synapse subtypes. This proposal will (1) determine the mechanisms underlying the formation of
postsynaptic inhibitory SSDs during activity-dependent synapse growth, (2) define the mechanisms and
functional relevance of postsynaptic SSD clustering opposite presynaptic release sites, and (3) examine how
subcellular location and interneuron input influence inhibitory nanoscale organization. These aims will test our
overarching hypothesis that inhibitory synaptic nanoscale organization underlies inhibitory synaptic strength,
and its dynamic regulation is a crucial mechanism for synaptic plasticity. These proposed studies will be
significant, being the first comprehensive mechanistic and functional examination of inhibitory synapse
architecture at nanoscale resolution (in both culture and slice) and in real-time during short- and long-term
plasticity paradigms. The widespread importance of this work is that it will greatly expand our understanding of
the detailed mechanisms that control inhibitory synaptic plasticity and inhibition, which is critical for maintaining
E/I balance and neuronal function. Moreover, determining the nanoscale structure of inhibitory synapses in
healthy brains will pave the way for future studies i...

## Key facts

- **NIH application ID:** 10292962
- **Project number:** 5R01MH119154-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Katharine Rachel Smith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $383,700
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10292962

## Citation

> US National Institutes of Health, RePORTER application 10292962, Nanoscale organization of the inhibitory synapse during synaptic plasticity (5R01MH119154-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10292962. Licensed CC0.

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