# Neurotrophin-dependent regulation of voltage-gated sodium channels

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2020 · $622,966

## Abstract

ABSTRACT
Neuropsychiatric disorders are thought to arise from complex changes of brain plasticity. Recent evidence
points toward ion channel complexes as cellular hubs of plasticity that confer disease vulnerability or protection
depending on the channel regulatory state. In medium spiny neurons (MSNs) in the nucleus accumbens (NAc),
a subtype of highly vulnerable cells, neuroadaptive changes in intrinsic firing are mediated by neurotrophin
brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling.
Yet, the molecular
mechanisms by which these changes occur are still poorly understood.
Intrinsic firing in MSN relies on the integrity of the macromolecular complex of the voltage-gated Na+ (Nav)
channel Nav1.6 and its accessory regulatory fibroblast growth factor 14 (FGF14) and is subject to regulation by
glycogen synthase kinase 3 (GSK3) β, a downstream effector of BDNF/TrkB signaling. Here, we provide
exciting new evidence for the Nav1.6, FGF14 and GSK3β as a macromolecular signaling complex downstream
of BDNF/TrkB critical for MSNs neuronal plasticity. Using an array of in vitro and in cell assays, cell imaging,
and electrophysiology, we show that stability, phosphorylation and functional activity of the Nav1.6 channel are
proportional to the level of BDNF and the kinase activity, whereby low level of
BDNF predicts resilience and
high level mediates a susceptible phenotype conferred by changes in neuron firing. We will conduct a full
range of biophysical, biochemical and electrophysiological studies combined with pharmacological and viral
vector-based in vivo gene transfer methods to evaluate the impact of BDNF/TrkB signaling on macromolecular
composition (Aim 1), subcellular targeting (Aim 2) and functional properties (Aim 3) of the Nav1.6 channel in
the context of neuroadaptive plasticity of MSNs. Outcomes of these studies could potentially lead to the
development of biomarkers of susceptibility to neuropsychiatric disorders by investigating molecular pathways
in relevant experimental models, an area of great interest for biological psychiatry.

## Key facts

- **NIH application ID:** 10072704
- **Project number:** 1R01MH124351-01
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Fernanda Laezza
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $622,966
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072704

## Citation

> US National Institutes of Health, RePORTER application 10072704, Neurotrophin-dependent regulation of voltage-gated sodium channels (1R01MH124351-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10072704. Licensed CC0.

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