Gene therapy with doxycycline-controlled expression of human Kv1.1 reduces neuronal excitability and increases sociability of Scn2a-deficient mice
- 1Purdue University
Abstract
Genetic loss-of-function (LoF) variants in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been identified as one of the foremost monogenic causes of autism spectrum disorder (ASD). ASD encompasses a broad spectrum of behavioral phenotypes, with impaired sociability as a core characteristic. We have established Scn2a-deficient mice (Scn2agt/gt) to model Scn2a-related ASD and found that this model recapitulates social impairment, exhibiting severe social deficits. Scn2agt/gt mice exhibit neuronal hyperexcitability and a marked global reduction in potassium channel expression, which plays a crucial role in maintaining the resting membrane potential and repolarizing neurons after an action potential. Among these downregulated potassium channels, potassium voltage-gated channel subfamily A member 1 (Kv1.1) was one of the most affected. To explore whether Kv1.1 could be a potential therapeutic target in SCN2A-related ASD, we evaluated the in vivo efficacy of a genetic construct driven by the CaMKII promoter that allows for exogenous expression of human Kv1.1 (hKv1.1) in principal neurons. In Scn2agt/gt mice, we found that hKv1.1 expression normalizes neuronal hyperexcitability. Importantly, doxycycline-induced hKv1.1 expression enhances sociability in Scn2a-deficient mice without influencing social behavior in wild-type mice, and this effect was reversed upon doxycycline withdrawal. Overall, we demonstrate the successful use of an inducible AAV-mediated gene delivery system to supplement hKv1.1 expression to mitigate neuronal hyperexcitability and ameliorate social impairments in a mouse model of SCN2A-related ASD. These findings highlight the contribution of Kv1.1 to SCN2A-associated pathophysiology and its potential as a therapeutic target for severe social deficits.
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BibTeX
@misc{deming2026gene,
title = {{Gene therapy with doxycycline-controlled expression of human Kv1.1 reduces neuronal excitability and increases sociability of Scn2a-deficient mice}},
author = {B. A. Deming and J. Zhang and I. Vitko and R. P. Gaykema and M. Halurkar and Z. Zhang and A. D. Abeyaratna and R. Ranga and P. Mandal and K. Lund and K. Farmer and D. Ramasamy and E. Perez-Reyes and Y. Yang},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.22.753612},
url = {https://www.biorxiv.org/content/10.64898/2026.09.22.753612v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Gene therapy with doxycycline-controlled expression of human Kv1.1 reduces neuronal excitability and increases sociability of Scn2a-deficient mice
AU - B. A. Deming
AU - J. Zhang
AU - I. Vitko
AU - R. P. Gaykema
AU - M. Halurkar
AU - Z. Zhang
AU - A. D. Abeyaratna
AU - R. Ranga
AU - P. Mandal
AU - K. Lund
AU - K. Farmer
AU - D. Ramasamy
AU - E. Perez-Reyes
AU - Y. Yang
PY - 2026
DA - 2026/09/22
PB - bioRxiv
DO - 10.64898/2026.09.22.753612
UR - https://www.biorxiv.org/content/10.64898/2026.09.22.753612v1
AB - Genetic loss-of-function (LoF) variants in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been identified as one of the foremost monogenic causes of autism spectrum disorder (ASD). ASD encompasses a broad spectrum of behavioral phenotypes, with impaired sociability as a core characteristic. We have established Scn2a-deficient mice (Scn2agt/gt) to model Scn2a-related ASD and found that this model recapitulates social impairment, exhibiting severe social deficits. Scn2agt/gt mice exhibit neuronal hyperexcitability and a marked global reduction in potassium channel expression, which plays a crucial role in maintaining the resting membrane potential and repolarizing neurons after an action potential. Among these downregulated potassium channels, potassium voltage-gated channel subfamily A member 1 (Kv1.1) was one of the most affected. To explore whether Kv1.1 could be a potential therapeutic target in SCN2A-related ASD, we evaluated the in vivo efficacy of a genetic construct driven by the CaMKII promoter that allows for exogenous expression of human Kv1.1 (hKv1.1) in principal neurons. In Scn2agt/gt mice, we found that hKv1.1 expression normalizes neuronal hyperexcitability. Importantly, doxycycline-induced hKv1.1 expression enhances sociability in Scn2a-deficient mice without influencing social behavior in wild-type mice, and this effect was reversed upon doxycycline withdrawal. Overall, we demonstrate the successful use of an inducible AAV-mediated gene delivery system to supplement hKv1.1 expression to mitigate neuronal hyperexcitability and ameliorate social impairments in a mouse model of SCN2A-related ASD. These findings highlight the contribution of Kv1.1 to SCN2A-associated pathophysiology and its potential as a therapeutic target for severe social deficits.
ER -