# A phenotypic screen for compounds that differentially affect excitatory and inhibitory neuronal signaling

> **NIH NIH R44** · QUIVER BIOSCIENCE INC. · 2022 · $995,203

## Abstract

Project Summary: Maintaining the appropriate balance of excitation (E) vs. inhibition (I) in the
nervous system is essential for normal brain function, as disruptions in E/I balance are associated
with disorders such as autism spectrum disorder (ASD), schizophrenia, and seizures.
Development of therapeutics for ASD and schizophrenia has lagged due to their multifactorial
etiology and challenges in modeling relevant biology in scalable in vitro assays.
The Optopatch platform recently developed at Q-State Biosciences, which uses engineered
optogenetic proteins, custom microscopes, and software, makes it possible to simultaneously
stimulate (blue light) and record (red light) electrical activity from ~100 neurons with 1 millisecond
temporal resolution, single-cell spatial resolution and high signal-to-noise ratio. In addition to
measurements of intrinsic excitability, patterned blue light can be used to probe synaptic
connections by stimulating a subset of neurons and recording postsynaptic potentials (PSPs) in
all remaining cells. The Optopatch assays, which record signals in individual neurons, can be
paired with fluorescent labels of inhibitory neurons to identify compounds that differentially affect
signaling in excitatory and inhibitory cells and would be expected to shift the E/I balance.
In Phase I of this project, we propose to 1) adapt the established Q-State assays for intrinsic
excitability and synaptic transmission to measure the E/I balance and 2) validate these assays
using tool compounds and gene knockdowns expected to shift the E/I balance. In Phase II, we
propose to 3) screen annotated compound libraries, 4) confirm that proteins targeted by
compounds in the library can modulate the E/I balance, and 5) validate that identified targets can
also shift the E/I balance in human stem-cell derived neurons and in rodent brain slice. The
identified protein targets will serve as a starting point for drug discovery, and identified FDA-
approved compounds may be repurposed for new indications. The suite of tools developed here
will pave a new path for developing E/I-modulating therapeutics for treating complex neurological
disorders such as autism and schizophrenia.

## Key facts

- **NIH application ID:** 10019732
- **Project number:** 4R44MH121169-02
- **Recipient organization:** QUIVER BIOSCIENCE INC.
- **Principal Investigator:** James Fink
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $995,203
- **Award type:** 4N
- **Project period:** 2019-08-08 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10019732

## Citation

> US National Institutes of Health, RePORTER application 10019732, A phenotypic screen for compounds that differentially affect excitatory and inhibitory neuronal signaling (4R44MH121169-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10019732. Licensed CC0.

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