# Molecular Mechanisms of Electrical Synapse Formation in Vivo

> **NIH NIH R01** · UNIVERSITY OF OREGON · 2021 · $401,367

## Abstract

All of brain function, from sensory perception to behavior, is derived from the pattern and properties of the
synaptic connections among billions (in humans) of individual neurons. The long-term goal of this project is to
understand molecular pathways that regulate synapse formation in vivo using a vertebrate model with a focus
on the underappreciated electrical synapse. Electrical synapses are sites of direct communication between
neurons that allow the passage of ions and small molecules. They contribute extensively to neural circuit
formation and function, both during development as well in adulthood where they contribute to sensory
perception, interneuron processing, and motor output. However, the molecular mechanisms controlling the
formation of electrical synapse are poorly understood. This proposal utilizes the zebrafish Mauthner circuit to
investigate the genetics, cell biology, and biochemistry of electrical synapse formation and function. Mauthner
neurons are individually identifiable and their pre- and postsynaptic partners, synapses, and function are
exquisitely visualized in a living, vertebrate embryo. Classic forward and novel reverse genetic screens have
identified the Connexins that form the inter-neuronal channels of the Mauthner electrical synapses, found that
there are dedicated pre- and postsynaptic Connexins, and identified Neurobeachin, a post-Golgi trafficking
protein, and Tight Junction Protein 1b (Tjp1b), a membrane-associated guanylate kinase (MAGUK) family
scaffold, as being required for electrical synapse formation. These findings suggest that electrical synapses are
comprised of a molecular complexity that is not generally appreciated; they further suggests that intricate
biochemical mechanisms are required to control the formation, function, and plasticity of these critical sites of
neuronal communication. Aim1 of this proposal examines the cell biological mechanisms of electrical synapse
formation, examining the hypothesis that electrical synapses require the postsynaptic localization and function
of Tjp1b to stabilize Connexins at the synapse. Aim2 examines the biochemical mechanisms of
synaptogenesis, examining the hypothesis that a direct interaction between Tjp1b and the Connexins is
required for localization to the synapse. Aim3 looks to expand the molecular repertoire of proteins required for
electrical synapse formation, and provides a new view of electrical synapses as complex multi-molecular
machines. Given that electrical synapses are essential to early developmental wiring of the brain, they may be
intricately linked to developmental disorders of wiring. Indeed, both Neurobeachin and the MAGUKs are
associated with autism and other neurodevelopmental disorders. The proposed studies will provide novel
insight into the mechanisms of electrical synapse formation and provide a foundation for the identification of
targets for therapy of complex neurodevelopmental disorders.

## Key facts

- **NIH application ID:** 10079028
- **Project number:** 5R01NS105758-03
- **Recipient organization:** UNIVERSITY OF OREGON
- **Principal Investigator:** Adam C Miller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $401,367
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10079028

## Citation

> US National Institutes of Health, RePORTER application 10079028, Molecular Mechanisms of Electrical Synapse Formation in Vivo (5R01NS105758-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10079028. Licensed CC0.

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