# The role of gephyrin translation in inhibitory synaptic plasticity

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2022 · $36,212

## Abstract

PROJECT SUMMARY
Synaptic plasticity, the activity-dependent alteration in the strength of neuronal connections, forms the molecular
basis of learning, memory, and cognition. Both excitatory and inhibitory connections undergo bidirectional
synaptic plasticity to tune neuronal excitability, sculpt neural circuits, and coordinate the balance of excitation
and inhibition (E/I balance). GABAergic synaptic plasticity is crucial for maintaining E/I balance, and its
dysfunction is implicated in pathologies such as epilepsy, schizophrenia, and autism spectrum disorders.
However, inhibitory synaptic plasticity and its molecular underpinnings are critically understudied. A crucial
regulator of inhibitory synaptic plasticity is gephyrin, a synaptic scaffolding protein essential for GABAA receptor
clustering and inhibitory synaptic transmission. In one form of inhibitory synaptic plasticity, inhibitory long-term
potentiation (iLTP), gephyrin clustering increases rapidly at dendritic inhibitory synapses to strengthen
GABAergic synapses exclusively in dendrites by 20 min post-stimulation. Early mechanisms of iLTP are
independent of translation, but much less is known about iLTP persistence and how translation of key proteins
maintains iLTP. Answering these questions will provide insights into mechanisms of synaptic plasticity and how
changes in GABAergic synaptic strength shape neural circuits long-term. In this proposal, I will address this
knowledge gap by focusing on the role of gephyrin translation for maintaining iLTP and more specifically
where it occurs and how it is regulated to enact precise and persistent potentiation of inhibitory synaptic
connections. I hypothesize that local gephyrin translation supports iLTP exclusively in the dendrites and
that translational regulation of gephyrin influences gephyrin synaptic clustering and inhibitory synaptic
strength. I will utilize fluorescent in situ labeling of mRNA and visualization of actively translating proteins to
determine localization and translation of gephyrin transcripts in dendrites following iLTP (Aim 1). miR153 is a
short, non-coding transcript identified as a key regulator of gephyrin translation and implicated in learning,
memory, and cognition. By modulating its expression levels in neurons and employing a combination of
immunocytochemistry and electrophysiology, I will determine the impact of miR153 function on gephyrin
clustering and inhibitory synaptic strength during iLTP (Aim 2). Together, this approach will elucidate how the
localization and regulation of gephyrin translation impact specific and lasting changes to inhibitory synaptic
strength during iLTP and ultimately reveal the mechanisms driving inhibitory synaptic plasticity to maintain E/I
balance for proper neural function.

## Key facts

- **NIH application ID:** 10460032
- **Project number:** 1F31NS124108-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Theresa Marie Welle
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $36,212
- **Award type:** 1
- **Project period:** 2022-04-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10460032

## Citation

> US National Institutes of Health, RePORTER application 10460032, The role of gephyrin translation in inhibitory synaptic plasticity (1F31NS124108-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10460032. Licensed CC0.

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