# The encoding of proprioceptive signaling by Nav1.6

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $41,972

## Abstract

Project Summary: The long-term objective of this work is to define the molecular mechanisms
underlying proprioceptive signaling that are required for sensory-driven motor behaviors.
Proprioception encodes body and limb position, which is essential for purposeful movement. Yet, the
lack of tools to selectively target genes in proprioceptors, the sensory neurons that carry proprioceptive
signals, has impeded our understanding of the molecular mechanisms underlying this vital "sixth
sense." Voltage-gated sodium channels (NaVs) are critical for neuronal signaling in the nervous system,
and proprioceptors express three isoforms: NaV1.1, NaV1.6, and NaV1.7. We recently discovered that
loss of NaV1.1 in sensory neurons causes ataxic-like behaviors and abnormal limb positioning and
impaired proprioceptor transmission during static muscle stretch. While loss of NaV1.7 has no impact
on motor function in mice or humans, NaV1.6 is known to contribute to the function of brain neurons
involved in motor control. Thus, our lab created a sensory neuron-wide knock out of NaV1.6 and found
that these animals have extremely severe motor coordination deficits distinct from those observed in
NaV1.1 conditional knockout animals. This proposal will uncover the mechanistic role of NaV1.6 in
proprioceptive signaling by developing the first CRISPR/Cas9 intersectional genetic and viral strategy
to manipulate genes in selectively proprioceptors. The work outlined herein will test the central
hypothesis that the unique cellular localization patterns and intrinsic properties of NaV1.6 underly the
transmission of proprioceptive signals to spinal motor circuits for motor behaviors. I test this hypothesis
using the following mechanistic aims: Aim 1 will analyze the cellular distribution patterns of NaV1.6
channels in proprioceptive sensory neurons. Aim 2 will investigate how loss of NaV1.6 changes
proprioceptor biophysical properties and excitability. Aim 3 will leverage an intersectional gene knock
out model to investigate how acute deletion of NaV1.6 proprioceptors affects sensory-motor circuit
function and motor behaviors, overcoming a long-standing challenge in the field. NaV1.6 is associated
with brain-related diseases like epilepsy and autism spectrum disorder. Symptoms of these diseases
include motor-related deficits; however, our understanding of the mechanisms that give rise to these
comorbidities outside the brain is understudied. The proposed herein are directly in line with the goals
of NINDS as it will 1) advance our knowledge about mammalian proprioception and 2) shed new light
on critical roles of peripheral sensory neuron signaling in neurological disorders. Furthermore, this
proposal will not only provide critical me new training in molecular biology and biochemistry techniques,
but also offer the scientific community a new and exciting approach to gene manipulation in challenging-
to-target neuronal populations.

## Key facts

- **NIH application ID:** 10902905
- **Project number:** 1F31NS134241-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Cyrrus Maxwell Espino
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,972
- **Award type:** 1
- **Project period:** 2024-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10902905

## Citation

> US National Institutes of Health, RePORTER application 10902905, The encoding of proprioceptive signaling by Nav1.6 (1F31NS134241-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10902905. Licensed CC0.

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