# Elucidation of Nanostructure and Function of Spontaneous GABAergic Transmission at the Inhibitory Synapse

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2024 · $34,304

## Abstract

PROJECT SUMMARY
At the excitatory synapse, a heterogenous molecular layout creates a precise pre- and post-synaptic
structure that facilitates different modes of neurotransmission. The spatial segregation of neurotransmission
leads to the autonomous function of spontaneous glutamate release. The investigation into the
structure/function relationship at the excitatory synapse has facilitated the discovery of disease pathways
and targets for psychiatric disease intervention. However, aberrant inhibitory neurotransmission is also
implicated in numerous psychiatric illnesses including schizophrenia, depression, and anxiety. Despite the
fundamental importance of inhibitory neurotransmission in disease, few studies have investigated the
relationship between nanostructure and function at the inhibitory synapse. My preliminary data suggests a
segregation of action potential dependent and spontaneous neurotransmission at central inhibitory
GABAergic synapses, but how this segregation is achieved is unknown. Few studies have investigated the
inhibitory structure/function relationship due to the limited tools that allow for the selective manipulation of
different modes of inhibitory neurotransmission. I have generated preliminary data that a novel small
molecule drug, Artemisinin, selectively dysregulates inhibitory spontaneous release as it competitively binds
in the GABAAR-gephyrin binding pocket; providing a new pharmacological tool that will be utilized throughout
this proposal. This project will investigate the GABAergic synapse in two-fold by elucidating the post-synaptic
structure that segregates neurotransmission and how this structure leads to an autonomous function of
spontaneous GABAergic transmission in homeostatic plasticity. In primary hippocampal culture, Artemisinin
will be used as a tool to decrease GABAergic spontaneous release to investigate how this corresponds to
nanostructure and signaling pathways. The central hypothesis is GABAergic synapses have a specific post-
synaptic gephyrin scaffold and GABAAR nanostructure that facilitates an autonomous role of spontaneous
neurotransmission. Aim#1 will investigate how the post-synaptic structure segregates neurotransmission
using super resolution and electron microscopy to assess 1a. gephyrin clustering dynamics and 1b. GABAAR
subunit localization and clustering. Aim#2 will investigate the functional pathway this nanostructure
facilitates by delineating the role of spontaneous GABAergic neurotransmission in homeostatic plasticity.
2a. First downstream gene expression pathways will be assessed, specifically BDNF expression. 2b. Then
how spontaneous GABAergic signaling alters calcium dynamics to trigger gene transcription pathways will
be delineated. This research will elucidate the relationship between structure and function at the inhibitory
synapse, ultimately providing novel insight into the regulation of synaptic strength underlying
excitatory/inhibitory balance in health and disease.

## Key facts

- **NIH application ID:** 10844380
- **Project number:** 5F31MH132197-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Natalie Guzikowski
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $34,304
- **Award type:** 5
- **Project period:** 2023-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10844380

## Citation

> US National Institutes of Health, RePORTER application 10844380, Elucidation of Nanostructure and Function of Spontaneous GABAergic Transmission at the Inhibitory Synapse (5F31MH132197-02). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10844380. Licensed CC0.

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