# Precision editing of neural circuits using engineered electrical synapses

> **NIH NIH DP1** · DUKE UNIVERSITY · 2024 · $14,191

## Abstract

Abstract of funded grant DP1 (5DP1MH132709). Precision editing of neural circuits using engineered electrical
synapses Pioneering approaches including optogenetics and designer receptors exclusively activated by
designer drugs (DREADDs) enable the direct modulation of the activity of individual genetically defined cell types.
Nevertheless, it remains a fundamental challenge to selectively regulate the hallmark feature of neural circuits:
the interface between two specific brain cells. To address this challenge, we have created a new approach,
Long-term integration of circuits using Connexins (LinCx), that employs a novel pair of engineered connexin
hemichannels to directly modulate genetically defined neural circuits. When each member of the hemichannel
pair is expressed in two different cell(s)/cell-types that compose a circuit, they engage in heterotypic docking
(docking with each other) and an electrical synapse is constituted between the two cells. These pair of
hemichannels is engineered 1) to prevent them from engaging in homotypic docking (forming electrical synapses
with themselves), and 2) to disrupt them from docking with other connexin hemichannels endogenously
expressed in the mammalian brain. Finally, 3) the hemichannel pair exhibits rectification. Together, these three
properties confer LinCx with unprecedented spatial-, temporal-, and context precision, enabling the precise
editing of neural circuits. We propose to deploy LinCx across model organisms. We will determine the impact of
LinCx neuromodulation on neural circuit physiology and emotional behavior. We will also test whether LinCx
modulation is sufficient to restore normal behavior in animal models of psychiatric disorders. Successful
completion of these high-risk experiments will yield a new method for long-term circuit editing to regulate
emotional states in preclinical models. In the future, LinCx can be integrated with emerging viral tools that enable
systemic delivery of genetically encoded proteins to specific brain cell-types. Thus, LinCx also has an attainable
path to human translation for ameliorating devastating psychiatric disorders.

## Key facts

- **NIH application ID:** 11010687
- **Project number:** 3DP1MH132709-02S1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Kafui Dzirasa
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $14,191
- **Award type:** 3
- **Project period:** 2022-09-08 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11010687

## Citation

> US National Institutes of Health, RePORTER application 11010687, Precision editing of neural circuits using engineered electrical synapses (3DP1MH132709-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11010687. Licensed CC0.

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