The Autism-Associated Gene Scn2a Contributes to Dendritic Excitability and Synaptic Function in the Prefrontal Cortex
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Abstract
Autism spectrum disorder (ASD) is strongly associated with de novo gene mutations. One of the most commonly affected genes is SCN2A. ASD-associated SCN2A mutations impair the encoded protein Na V 1.2, a sodium channel important for action potential initiation and propagation in developing excitatory cortical neurons. The link between an axonal sodium channel and ASD, a disorder typically attributed to synaptic or transcriptional dysfunction, is unclear. Here we show that Na V 1.2 is unexpectedly critical for dendritic excitability and synaptic function in mature pyramidal neurons in addition to regulating early developmental axonal excitability. Na V 1.2 loss reduced action potential backpropagation into dendrites, impairing synaptic plasticity and synaptic strength, even when Na V 1.2 expression was disrupted in a cell-autonomous fashion late in development. These results reveal a novel dendritic function for Na V 1.2, providing insight into cellular mechanisms probably underlying circuit and behavioral dysfunction in ASD.
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Synaptic dysfunction and excitation/inhibition imbalance is a common pathophysiological feature of multiple ASD models.
“Synaptic dysfunction and excitation/inhibition imbalance is identified as a common pathophysiological feature of multiple ASD models 137–139.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [138]
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Johnson, K. W., Herold, K. F., Milner, T. A., Hemmings, H. C., & Platholi, J. (2017) · The Journal of Comparative Neurology · doi:10.1002/cne.24291 · Cited by 19 · see citing works
皮質第5層錐体ニューロンにおける電位依存性コンダクタンスによる軸索と体細胞静止電位の差次的制御【Powered by NICT】
Wenqin, H., & Bruce, P. B. (2018) · Neuron · Cited by 15 · see citing works
Broca's region revisited: Cytoarchitecture and intersubject variability
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Research works printed but not linked: 1
- Satterstrom FK, Kosmicki JA, Wang J, Breen MS, Rubeis S De, An J-Y, Peng M, Collins RL, Grove J, Klei L, (2018). Novel genes for autism implicate both excitatory and inhibitory cell lineages in risk. BioRxiv 484113.
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Yan, Z., & Rein, B. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01092-3 · Cited by 300 · see citing works
Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum
Guerrini, R., Conti, V., Mantegazza, M., Balestrini, S., Galanopoulou, A. S., & Benfenati, F. (2023) · Physiological Reviews · doi:10.1152/physrev.00063.2021 · Cited by 196 · see citing works
Li, M., Jancovski, N., Jafar-Nejad, P., Burbano, L. E., Rollo, B., Richards, K., Drew, L., Sedo, A., Heighway, J., Pachernegg, S., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci152079 · Cited by 115 · see citing works
Recent advances in gene therapy for neurodevelopmental disorders with epilepsy
Turner, T. J., Zourray, C., Schorge, S., & Lignani, G. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15168 · Cited by 71 · see citing works
Stein, D., Kars, M. E., Wu, Y., Bayrak, Ç. S., Stenson, P. D., Cooper, D. N., Schlessinger, A., & Itan, Y. (2023) · Genome Medicine · doi:10.1186/s13073-023-01261-9 · Cited by 53 · see citing works
Mechanisms Underlying Circuit Dysfunction in Neurodevelopmental Disorders
Exposito-Alonso, D., & Rico, B. (2022) · Annual Review of Genetics · doi:10.1146/annurev-genet-072820-023642 · Cited by 49 · see citing works
Yoo, Y.-E., Mandal, P., Tang, Z., Zhang, Z., Zhang, J., Chen, X., Robinson, M., Eaton, M., Deming, B., Halurkar, M., et al. (2025) · doi:10.1101/2025.09.16.676420 · Cited by 1 · see citing works
- Authors
- Spratt, P. W. E., Ben-Shalom, R., Keeshen, C. M., Burke, K. J., Clarkson, R. L., Sanders, S. J., & Bender, K. J.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Bender, Kevin J.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 103
- Issue
- 4
- Pages
- 673-685.e5
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC7935470
- OpenAlex
- W2950333680
- Cited by
- 244
- References
- 93
- Citations by year
- 2026: 29 · 2025: 48 · 2024: 39 · 2023: 33 · 2022: 22 · 2021: 39 · 2020: 24 · 2019: 8 · 2014: 1
- FWCI
- 7.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Natural Sciences and Engineering Research Council of Canada
- National Institutes of Health (F32 NS095580, R01 MH110928)
- Simons Foundation Autism Research Initiative (513133)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- SCN2A, Nav1.2 sodium channel, autism spectrum disorder, dendritic excitability, action potential backpropagation, synaptic plasticity, synaptic efficacy, pyramidal neurons, prefrontal cortex, de novo mutations, cortical excitatory neurons
- MeSH terms
- Autism Spectrum Disorder, Action Potentials, Animals, Dendrites, Female, Heterozygote, Hippocampus, Male, Social Behavior, Protein Engineering, N-Methylaspartate, Prefrontal Cortex, Pyramidal Cells, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, Gene Expression Regulation, Developmental, Maze Learning, Neocortex, Calcium Signaling, Mice, Miniature Postsynaptic Potentials, NAV1.2 Voltage-Gated Sodium Channel
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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