# Exploring the role of oxytocin in the regulation of neuronal excitability

> **NIH NIH R01** · EMORY UNIVERSITY · 2022 · $474,192

## Abstract

PROJECT SUMMARY
Dysfunction of voltage-gated sodium channels (VGSCs) is responsible for several forms of catastrophic
childhood encephalopathies. Over 1000 loss-of-function mutations in the VGSC SCN1A have been identified
during the last two decades and are the main cause of Dravet syndrome (DS), characterized by recurrent early-
life febrile seizures (FSs), severe afebrile epilepsy, cognitive and behavioral deficits, and a 15-20% mortality
rate. Mutations in the VGSC SCN8A were more recently identified in 2012, and already over 200 gain-of-function
SCN8A mutations have been reported in patients with a range of clinical features including catastrophic
treatment-resistant childhood epilepsy, autism, intellectual disability and developmental delay. Unfortunately,
most anti-epileptic drugs (AEDs) fail to adequately treat the broad range of severe seizures and behavioral
phenotypes in patients with SCN1A- and SCN8A-derived epilepsy. Thus, despite recent progress in
pharmacological treatments for DS, there remains a need to develop more effective, longer lasting treatments
with fewer side effects. Neuropeptides are well known in animal studies to show great promise for controlling
seizures and ameliorating behavioral abnormalities; however, they do not readily cross the blood brain barrier
and are rapidly metabolized when given systemically. Thus, poor brain penetrance is a critical barrier to the
clinical application of these promising therapeutics. To overcome this challenge, we developed and validated an
approach based on the encapsulation of neuropeptides in nanoparticles conjugated to rabies virus glycoprotein
(RVG). Using this approach, we have found that intranasal delivery of nanoparticle-encapsulated oxytocin (NP-
OT) greatly increases brain penetrance and the capacity of OT to confer robust and sustained increases in
resistance to seizures in mouse models of SCN1A and SCN8A dysfunction. We have also extended our strategy
to encapsulate neuropeptide Y (NP-NPY), and similarly observed a robust improvement in its ability to confer
seizure resistance. In the proposed study, we will establish the ability of NP-OT and NP-NPY to ameliorate
spontaneous seizures and behavioral abnormalities in Scn1a and Scn8a mouse mutants (Aim 1). While the role
of OT in social behavior is well-studied, less is known about the mechanisms by which it modulates seizure
susceptibility. Thus, we will also identify the cellular and neural circuit mechanisms that contribute to the ability
of OT to increase seizure resistance in the Scn1a and Scn8a mutants (Aim 2). Our long-term goal is to develop
safe and effective approaches for the brain delivery of neuropeptides for the treatment of epilepsy and other
neurological disorders.

## Key facts

- **NIH application ID:** 10397642
- **Project number:** 5R01NS120676-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Andrew P Escayg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $474,192
- **Award type:** 5
- **Project period:** 2021-05-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10397642

## Citation

> US National Institutes of Health, RePORTER application 10397642, Exploring the role of oxytocin in the regulation of neuronal excitability (5R01NS120676-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10397642. Licensed CC0.

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