Single-nucleus transcriptomics reveals disrupted pathways in the prefrontal cortex of Scn2a-deficient mice
8 affiliations
- 1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN USA
- 2Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN USA
- 3School of Health Sciences, Purdue University, West Lafayette, IN USA
- 4Purdue Institute for Cancer Research, West Lafayette, IN 47907 USA
- 5Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202 USA
- 6Center for Medical Genomics, Indiana University School of Medicine, Indianapolis, IN USA
- 7Davidson School of Chemical Engineering, West Lafayette, IN USA
- 8Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN USA
Abstract
Loss-of-function variants in SCN2A, which encodes the NaV1.2 sodium channel critical for action potential initiation and backpropagation, are associated with autism spectrum disorder (ASD) and epilepsy. To investigate SCN2A deficiency–related phenotypes, we developed a preclinical mouse model with severe NaV1.2 deficiency, which exhibits robust behavioral abnormalities related to autism and epilepsy. However, the neuronal populations and molecular alterations in the mouse model have not been investigated at single-cell resolution. In this study, we performed single-nucleus RNA sequencing (snRNA-seq) in wild-type (WT), homozygous Scn2a-deficient (HOM), and Scn2a-restored HOM (HOM-FlpO) mice. We then examined how Scn2a expression levels affect cellular composition and gene expression profiles in the medial prefrontal cortex (mPFC), a brain region implicated in ASD. Intriguingly, we observed an increased population of immature GABAergic neurons in adult HOM mice, whereas this population is nearly absent in adult WT mice. Differential expression analysis of GABAergic and glutamatergic neurons across genotypes also revealed widespread changes in genes associated with neurotransmitter regulation and synapse organization. Analysis of the HOM-FlpO data identified genes that were significantly altered in HOM mice and were restored toward WT levels following adult Scn2a restoration. Together, these results indicate that reduced Scn2a expression disrupts global transcriptomic profiles across multiple neural cell types, providing insight into cell–type–specific mechanisms underlying SCN2A-related disorders.
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BibTeX
@article{yoo2026singlenucleus,
title = {{Single-nucleus transcriptomics reveals disrupted pathways in the prefrontal cortex of Scn2a-deficient mice}},
author = {Ye-Eun Yoo and Zaiyang Zhang and Purba Mandal and Zhengkuan Tang and Jingliang Zhang and Xiaoling Chen and Morgan Robinson and Muriel Eaton and Brody Deming and Manasi Halurkar and Harish Kothandaraman and Luke C. Dabin and Boyu Jiang and Hongyu Gao and Chongli Yuan and Nadia Lanman and Yunlong Liu and Jungsu Kim and Priyanka Baloni and Yang Yang},
journal = {Translational Psychiatry},
year = {2026},
month = jul,
doi = {10.1038/s41398-026-04348-0},
url = {https://doi.org/10.1038/s41398-026-04348-0},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Single-nucleus transcriptomics reveals disrupted pathways in the prefrontal cortex of Scn2a-deficient mice
AU - Ye-Eun Yoo
AU - Zaiyang Zhang
AU - Purba Mandal
AU - Zhengkuan Tang
AU - Jingliang Zhang
AU - Xiaoling Chen
AU - Morgan Robinson
AU - Muriel Eaton
AU - Brody Deming
AU - Manasi Halurkar
AU - Harish Kothandaraman
AU - Luke C. Dabin
AU - Boyu Jiang
AU - Hongyu Gao
AU - Chongli Yuan
AU - Nadia Lanman
AU - Yunlong Liu
AU - Jungsu Kim
AU - Priyanka Baloni
AU - Yang Yang
PY - 2026
DA - 2026/07/31
JO - Translational Psychiatry
DO - 10.1038/s41398-026-04348-0
UR - https://doi.org/10.1038/s41398-026-04348-0
AB - Loss-of-function variants in SCN2A, which encodes the NaV1.2 sodium channel critical for action potential initiation and backpropagation, are associated with autism spectrum disorder (ASD) and epilepsy. To investigate SCN2A deficiency–related phenotypes, we developed a preclinical mouse model with severe NaV1.2 deficiency, which exhibits robust behavioral abnormalities related to autism and epilepsy. However, the neuronal populations and molecular alterations in the mouse model have not been investigated at single-cell resolution. In this study, we performed single-nucleus RNA sequencing (snRNA-seq) in wild-type (WT), homozygous Scn2a-deficient (HOM), and Scn2a-restored HOM (HOM-FlpO) mice. We then examined how Scn2a expression levels affect cellular composition and gene expression profiles in the medial prefrontal cortex (mPFC), a brain region implicated in ASD. Intriguingly, we observed an increased population of immature GABAergic neurons in adult HOM mice, whereas this population is nearly absent in adult WT mice. Differential expression analysis of GABAergic and glutamatergic neurons across genotypes also revealed widespread changes in genes associated with neurotransmitter regulation and synapse organization. Analysis of the HOM-FlpO data identified genes that were significantly altered in HOM mice and were restored toward WT levels following adult Scn2a restoration. Together, these results indicate that reduced Scn2a expression disrupts global transcriptomic profiles across multiple neural cell types, providing insight into cell–type–specific mechanisms underlying SCN2A-related disorders.
SN - 2158-3188
ER -