# An optogenetic tool for acute modulation of inhibitory synaptic function

> **NIH NIH F32** · UNIVERSITY OF COLORADO DENVER · 2020 · $65,310

## Abstract

The brain responds to experiences in the world through the modification of individual synapses. Changes to
synaptic architecture underlie the cellular basis for learning and memory and synaptic dysfunction results in a
range of neurodevelopmental and psychiatric disorders including epilepsy, autisms, and schizophrenia. The
strength of synaptic connections is governed by the underlying molecular architecture at the post-synaptic
density; neurotransmitter receptors, adhesion proteins, signaling molecules and cytoskeletal elements all interact
in transient and highly regulated ways to shape neurotransmission. Modular scaffolding proteins play a decisive
role in this organization. Recent studies at glutamatergic excitatory synapses have demonstrated that
postsynaptic scaffolding proteins are not homogeneously distributed but instead are clustered near pre-synaptic
active zones into subsynaptic “nanodomains” within the postsynaptic membrane. This organization is thought to
facilitate fast, efficient transmission. The subsynaptic organization of inhibitory synapses remains poorly
characterized, although analogous principles likely apply. The functional significance of this nano-scale
organization at either excitatory or inhibitory synapses remains unclear due to a lack of tools for inducibly
and reversibly disrupting molecular architecture while simultaneously measuring synaptic function.
In this proposal I will address this using a novel optogenetic approach we have developed for rapidly (within
seconds) and reversibly (within minutes) perturbing the nanoscale architecture of the major inhibitory
postsynaptic scaffolding protein Gephyrin. I will utilize the optical dimerization protein CRY2olig, which self-
oligomerizes within seconds of exposure to 488 nm light12, attached to an intrabody against gephyrin (CRY2olig-
GephIB). This novel optogenetic tool provides an approach to acutely perturb endogenous gephyrin organization
in real time. In preliminary experiments we find a robust and persistent decrease to inhibitory synaptic strength
in cells expressing CRY2olig-GephIB within 60-120 seconds of photo induced cross-linking. I will use this
optogenetic tool in combination with live cell imaging, electrophysiology and super-resolution microscopy to
directly test the effect of manipulating subsynaptic scaffolding domains on synaptic transmission. This
approach will not only provide novel insight into synaptic function but will also fill a major gap in the optogenetic
toolkit for new approaches studying circuit dynamics through rapid and direct manipulation of synaptic strength.

## Key facts

- **NIH application ID:** 10069044
- **Project number:** 1F32MH123053-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Samantha Olah
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 1
- **Project period:** 2020-11-28 → 2023-11-27

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10069044

## Citation

> US National Institutes of Health, RePORTER application 10069044, An optogenetic tool for acute modulation of inhibitory synaptic function (1F32MH123053-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10069044. Licensed CC0.

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