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Cited by 9Epilepsy research and treatmentIon channel regulation and functionGenetics and Neurodevelopmental Disorders

Deciphering SCN2A : A comprehensive review of rodent models of Scn2a dysfunction

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Scott, Katelin E. J., Hermosillo Arrieta, Maria Fernanda, Williams, Aislinn J.·2025·Epilepsia
DOI 10.1111/epi.18615PMC PMC12779317
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Abstract

SCN2A encodes for the alpha subunit of the voltage‐gated sodium channel Na V 1.2, which is involved in action potential initiation and backpropagation in excitatory neurons. Currently, it is one of the highest monogenetic risk factors for both epilepsy and autism spectrum disorder. However, SCN2A ‐related disorders manifest in a broad clinical neuropsychiatric spectrum, including distinct neurological and psychiatric disorders. This clinical heterogeneity presents challenges for mechanistic understanding and treatment development. SCN2A mutations are generally classified as either gain‐of‐function (GOF) or loss‐of‐function (LOF); however, many mutations do not perfectly align to this binary framework. SCN2A dysfunction alters neuronal excitability, channel kinetics, and synaptic transmission in various ways, resulting in multiple electrophysiological effects and both seizure and behavioral phenotypes that are influenced by developmental stage, brain region, genetic background, and sex. Although early lethality in GOF models limits behavioral characterization, LOF models broadly show patterns of learning impairments, altered sociability, and disrupted sensory processing. Still, behavioral and seizure phenotypes are often inconsistent even across models with similar or identical variants, suggesting that genetic modifiers, such as potassium channels, play a role in shaping disease outcomes. Overall, these findings suggest that SCN2A ‐related disorders involve complex gene–gene and gene–environment interactions, rather than only channel biophysics. Current therapeutic strategies include Clustered Regularly Interspaced Short Palindromic Repeat‐mediated transcriptional activation (CRISPRa), antisense oligonucleotides, and deep brain stimulation; however, they are limited due to variant specificity or age of intervention. This review highlights areas of convergence and conflict across models, emphasizing knowledge gaps, such as the limited availability of data on early development. Ultimately, it emphasizes the importance of investigating models across different developmental stages, using diverse genetic background strains, among other approaches, to encourage therapeutic innovation and enhance care for patients. We hope this work contributes to the emerging unifying framework that looks beyond the GOF and LOF binary in SCN2A ‐related disorders.

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  • Both gain-of-function and loss-of-function variants in SCN2A are associated with ASD, indicating that either excessive or insufficient excitability can perturb circuit development and function.

    “Both gain-of-function and loss-of-function (LoF) variants in SCN2A are associated with ASD, indicating that either excessive or insufficient excitability can perturb circuit development and function (Scott et al., 2025).”

    From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Scott et al., 2025

    The Background (page unavailable) associates SCN2A loss-of-function variants with autism, but says gain-of-function variants are often associated with early epilepsy; it does not establish an ASD association for both classes. The Abstract says SCN2A dysfunction alters excitability and synaptic transmission, but the claimed conclusion that both excessive and insufficient excitability perturb circuit development and function goes beyond what these passages establish. (LLM, conf=0.86)

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  1. [1]Lauxmann S, Verbeek NE, Liu Y, Zaichuk M, Müller S, Lemke JR, et al. Relationship of electrophysiological dysfunction and clinical severity in SCN2A ‐related epilepsies. Hum Mutat. 2018; 39: 1942– 1956. 30144217
  2. [2]Shi X, Yasumoto S, Kurahashi H, Nakagawa E, Fukasawa T, Uchiya S, et al. Clinical spectrum of SCN2A mutations. Brain Dev. 2012; 34: 541– 545. 22029951
  3. [3]Adney SK, Millichap JJ, DeKeyser JM, Abramova T, Thompson CH, George AL Jr. Functional and pharmacological evaluation of a novel SCN2A variant linked to early‐onset epilepsy. Ann Clin Transl Neurol. 2020; 7: 1488– 1501. 32750235 PMC7480906
  4. [4]Liao Y, Anttonen AK, Liukkonen E, Gaily E, Maljevic S, Schubert S, et al. SCN2A mutation associated with neonatal epilepsy, late‐onset episodic ataxia, myoclonus, and pain. Neurology. 2010; 75: 1454– 1458. 20956790
  5. [6]Sundaram SK, Chugani HT, Tiwari VN, Huq AHMM. SCN2A mutation is associated with infantile spasms and Bitemporal glucose Hypometabolism. Pediatr Neurol. 2013; 49: 46– 49. 23827426 PMC3868437
  6. [7]Murray M, Martindale JM, Otallah SI. SCN2A ‐ associated episodic and persistent ataxia with cerebellar atrophy: a case report. Child Neurol Open. 2023; 10: 2329048X2311639. PMC10026144 36950068
  7. [8]Ben‐Shalom R, Keeshen CM, Berrios KN, An JY, Sanders SJ, Bender KJ. Opposing effects on NaV1.2 function underlie differences between SCN2A variants observed in individuals with autism Spectrum disorder or infantile seizures. Biol Psychiatry. 2017; 82: 224– 232. 28256214 PMC5796785
  8. [9]Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, et al. De novo mutations revealed by whole‐exome sequencing are strongly associated with autism. Nature. 2012; 485: 237– 241. 22495306 PMC3667984
  9. [11]Li J, Cai T, Jiang Y, Chen H, He X, Chen C, et al. Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database. Mol Psychiatry. 2016; 21: 290– 297. 25849321 PMC4837654
  10. [12]Begemann A, Acuña MA, Zweier M, Vincent M, Steindl K, Bachmann‐Gagescu R, et al. Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes. Mol Med. 2019; 25: 6. 30813884 PMC6391808
  11. [13]Carroll LS, Woolf R, Ibrahim Y, Williams HJ, Dwyer S, Walters J, et al. Mutation screening of SCN2A in schizophrenia and identification of a novel loss‐of‐function mutation. Psychiatr Genet. 2016; 26: 60– 65. 26555645 PMC4756433
  12. [14]Suddaby JS, Silver J, So J. Understanding the schizophrenia phenotype in the first patient with the full SCN2A phenotypic spectrum. Psychiatr Genet. 2019; 29: 91– 94. 30741786
  13. [15]Hu W, Tian C, Li T, Yang M, Hou H, Shu Y. Distinct contributions of Nav1.6 and Nav1.2 in action potential initiation and backpropagation. Nat Neurosci. 2009; 12: 996– 1002. 19633666
  14. [16]Berecki G, Howell KB, Heighway J, Olivier N, Rodda J, Overmars I, et al. Functional correlates of clinical phenotype and severity in recurrent SCN2A variants. Commun Biol. 2022; 5: 1– 13. 35637276 PMC9151917
  15. [17]Wolff M, Brunklaus A, Zuberi SM. Phenotypic spectrum and genetics of SCN2A‐related disorders, treatment options, and outcomes in epilepsy and beyond. Epilepsia. 2019; 60(Suppl 3): S59– S67. 31904126
  16. [18]Miao P, Tang S, Ye J, Wang J, Lou Y, Zhang B, et al. Electrophysiological features: the next precise step for SCN2A developmental epileptic encephalopathy. Mol Genet Genomic Med. 2020; 8: e1250. 32400968 PMC7336724
  17. [19]Crawford K, Xian J, Helbig KL, Galer PD, Parthasarathy S, Lewis‐Smith D, et al. Computational analysis of 10,860 phenotypic annotations in individuals with SCN2A‐related disorders. Genet Med. 2021; 23: 1263– 1272. 33731876 PMC8257493
  18. [20]Berecki G, Howell KB, Deerasooriya YH, Cilio MR, Oliva MK, Kaplan D, et al. Dynamic action potential clamp predicts functional separation in mild familial and severe de novo forms of SCN2A epilepsy. Proc Natl Acad Sci. 2018; 115: E5516– E5525. 29844171 PMC6004444
  19. [21]Wolff M, Johannesen KM, Hedrich UBS, Masnada S, Rubboli G, Gardella E, et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A‐related disorders. Brain J Neurol. 2017; 140: 1316– 1336. 28379373
  20. [22]Echevarria‐Cooper DM, Hawkins NA, Misra SN, Huffman AM, Thaxton T, Thompson CH, et al. Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2a K1422E mice. Hum Mol Genet. 2022; 31: 2964– 2988. 35417922 PMC9433730
  21. [23]Yang X‐R, Ginjupalli VKM, Theriault O, Poulin H, Appendino JP, Au PYB, et al. SCN2A‐related epilepsy of infancy with migrating focal seizures: report of a variant with apparent gain‐ and loss‐of‐function effects. J Neurophysiol. 2022; 127: 1388– 1397. 35417276 PMC9109789
  22. [24]Abbott M, Bender KJ, Brunklaus A, Demarest S, Egan S, Haviland I, et al. SCN2A‐related disorders. Elements in Genetic Epilepsy. Cambridge: Cambridge University Press; 2025, pp. 1– 43. 10.1017/9781009530361 · DOI
  23. [25]Hedrich UBS, Lauxmann S, Lerche H. SCN 2A channelopathies: mechanisms and models. Epilepsia. 2019; 60: S68– S76. 31904120
  24. [26]Kruth KA, Grisolano TM, Ahern CA, Williams AJ. SCN2A channelopathies in the autism spectrum of neuropsychiatric disorders: a role for pluripotent stem cells? Mol Autism. 2020; 11: 23. 32264956 PMC7140374
  25. [27]Planells‐Cases R, Caprini M, Zhang J, Rockenstein EM, Rivera RR, Murre C, et al. Neuronal death and perinatal lethality in voltage‐gated Sodium Channel αII‐deficient mice. Biophys J. 2000; 78: 2878– 2891. 10827969 PMC1300874
  26. [28]Spratt PWE, Ben‐Shalom R, Keeshen CM, Burke KJ Jr, Clarkson RL, Sanders SJ, et al. The autism‐associated gene Scn2a contributes to dendritic excitability and synaptic function in the prefrontal cortex. Neuron. 2019; 103: 673– 685.e5. 31230762 PMC7935470
  27. [30]Gazina EV, Leaw BTW, Richards KL, Wimmer VC, Kim TH, Aumann TD, et al. ‘Neonatal’ Nav1.2 reduces neuronal excitability and affects seizure susceptibility and behaviour. Hum Mol Genet. 2015; 24: 1457– 1468. 25378553
  28. [31]Spratt PWE, Alexander RPD, Ben‐Shalom R, Sahagun A, Kyoung H, Keeshen CM, et al. Paradoxical hyperexcitability from NaV1.2 sodium channel loss in neocortical pyramidal cells. Cell Rep. 2021; 36: 109483. 34348157 PMC8719649
  29. [32]Bender KJ, Trussell LO. The physiology of the axon initial segment. Annu Rev Neurosci. 2012; 35: 249– 265. 22443507
  30. [33]Miyamoto H, Tatsukawa T, Shimohata A, Yamagata T, Suzuki T, Amano K, et al. Impaired cortico‐striatal excitatory transmission triggers epilepsy. Nat Commun. 2019; 10: 1917. 31015467 PMC6478892
  31. [34]Ogiwara I, Miyamoto H, Tatsukawa T, Yamagata T, Nakayama T, Atapour N, et al. Nav1.2 haplodeficiency in excitatory neurons causes absence‐like seizures in mice. Commun Biol. 2018; 1: 1– 16. 30175250 PMC6115194
  32. [35]Yamagata T, Ogiwara I, Mazaki E, Yanagawa Y, Yamakawa K. Nav1.2 is expressed in caudal ganglionic eminence‐derived disinhibitory interneurons: mutually exclusive distributions of Nav1.1 and Nav1.2. Biochem Biophys Res Commun. 2017; 491: 1070– 1076. 28784306
  33. [36]Wilbers R, Metodieva VD, Duverdin S, Heyer DB, Galakhova AA, Mertens EJ, et al. Human voltage‐gated Na+ and K+ channel properties underlie sustained fast AP signaling. Sci Adv. 2023; 9: eade3300. 37824607 PMC10569700
  34. [37]Higerd‐Rusli GP, Alsaloum M, Tyagi S, Sarveswaran N, Estacion M, Akin EJ, et al. Depolarizing NaV and hyperpolarizing KV channels are Co‐trafficked in sensory neurons. J Neurosci. 2022; 42: 4794– 4811. 35589395 PMC9188389
  35. [38]Li M, Eltabbal M, Tran H‐D, Kuhn B. Scn2a insufficiency alters spontaneous neuronal Ca2+ activity in somatosensory cortex during wakefulness. iScience. 2023; 26: 108138. 37876801 PMC10590963
  36. [39]Kotler O, Khrapunsky Y, Shvartsman A, Dai H, Plant LD, Goldstein SAN, et al. SUMOylation of NaV1.2 channels regulates the velocity of backpropagating action potentials in cortical pyramidal neurons. elife. 2023; 12: e81463. 36794908 PMC10014073
  37. [40]Plant LD, Marks JD, Goldstein SA. SUMOylation of NaV1.2 channels mediates the early response to acute hypoxia in central neurons. elife. 2016; 5: e20054. 28029095 PMC5283832
  38. [41]Onwuli DO, Beltran‐Alvarez P. An update on transcriptional and post‐translational regulation of brain voltage‐gated sodium channels. Amino Acids. 2016; 48: 641– 651. 26503606 PMC4752963
  39. [42]Wang C, Derderian KD, Hamada E, Zhou X, Nelson AD, Kyoung H, et al. Impaired cerebellar plasticity hypersensitizes sensory reflexes in SCN2A‐associated ASD. Neuron. 2024; 112: 1444– 1455.e5. 38412857 PMC11065582
  40. [43]Carson TB, Wilkes BJ, Patel K, Pineda JL, Ko JH, Newell KM, et al. Vestibulo‐ocular reflex function in children with high‐functioning autism spectrum disorders. Autism Res. 2017; 10: 251– 266. 27220548
  41. [44]Nunes D, Kuner T. Axonal sodium channel NaV1.2 drives granule cell dendritic GABA release and rapid odor discrimination. PLoS Biol. 2018; 16: e2003816. 30125271 PMC6117082
  42. [45]Léna I, Mantegazza M. NaV1.2 haploinsufficiency in Scn2a knock‐out mice causes an autistic‐like phenotype attenuated with age. Sci Rep. 2019; 9: 12886. 31501495 PMC6733925
  43. [46]Eaton M, Zhang J, Ma Z, Park AC, Lietzke E, Romero CM, et al. Generation and basic characterization of a gene‐trap knockout mouse model of Scn2a with a substantial reduction of voltage‐gated sodium channel Na v 1.2 expression. Genes Brain Behav. 2021; 20: e12725. 33369088
  44. [47]Zhang J, Chen X, Eaton M, Wu J, Ma Z, Lai S, et al. Severe deficiency of the voltage‐gated sodium channel NaV1.2 elevates neuronal excitability in adult mice. Cell Rep. 2021; 36: 109495. 34348148 PMC8382316
  45. [48]Bergren SK, Chen S, Galecki A, Kearney JA. Genetic modifiers affecting severity of epilepsy caused by mutation of sodium channelScn2a. Mamm Genome. 2005; 16: 683– 690. 16245025
  46. [49]Bergren SK, Rutter ED, Kearney JA. Fine mapping of an epilepsy modifier gene on mouse chromosome 19. Mamm Genome. 2009; 20: 359– 366. 19513789 PMC2804848
  47. [50]Schattling B, Fazeli W, Engeland B, Liu Y, Lerche H, Isbrandt D, et al. Activity of NaV1.2 promotes neurodegeneration in an animal model of multiple scleorosis. 2016. 10.1172/jci.insight.89810 PMC5111507 27882351 · DOI
  48. [51]Kearney JA, Plummer NW, Smith MR, Kapur J, Cummins TR, Waxman SG, et al. A gain‐of‐function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities. Neuroscience. 2001; 102: 307– 317. 11166117
  49. [52]Shin W, Kweon H, Kang R, Kim D, Kim K, Kang M, et al. Scn2a Haploinsufficiency in mice suppresses hippocampal neuronal excitability, excitatory synaptic drive, and long‐term potentiation, and spatial learning and memory. Front Mol Neurosci. 2019; 12: 145. 31249508 PMC6582764
  50. [53]Wu J, Zhang J, Chen X, Wettschurack K, Que Z, Deming BA, et al. Microglial over‐pruning of synapses during development in autism‐associated SCN2A‐deficient mice and human cerebral organoids. Mol Psychiatry. 2024; 29: 2424– 2437. 38499656
  51. [54]Gould E, Kim JH. SCN2A contributes to oligodendroglia excitability and development in the mammalian brain. Cell Rep. 2021; 36: 109653. 34496232 PMC8486143
  52. [55]Schamiloglu S, Wu H, Zhou M, Kwan AC, Bender KJ. Dynamic foraging behavior performance is not affected by Scn2a Haploinsufficiency. eNeuro. 2023; 10(12): 1– 13. PMC10755640 38151324
  53. [56]Li M, Jancovski N, Jafar‐Nejad P, Burbano LE, Rollo B, Richards K, et al. Antisense oligonucleotide therapy reduces seizures and extends life span in an SCN2A gain‐of‐function epilepsy model. J Clin Invest. 2021; 131: e152079. https://www.jci.org/articles/view/152079/pdf, 10.1172/JCI152079 34850743 PMC8631599 · DOI · Paper page
  54. [57]Echevarria‐Cooper DM, Hawkins NA, Kearney JA. Strain‐dependent effects on neurobehavioral and seizure phenotypes in Scn2aK1422E mice. 2023. 10.1101/2023.06.06.543929 · DOI
  55. [58]Kile KB, Tian N, Durand DM. Scn2a sodium channel mutation results in hyperexcitability in the hippocampus in vitro. Epilepsia. 2008; 49: 488– 499. 18031550 PMC2720056
  56. [59]Thompson CH, Hawkins NA, Kearney JA, George AL. CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice. Proc Natl Acad Sci USA. 2017; 114: 1696– 1701. 28137877 PMC5321040
  57. [60]Muller GK. The neonatal SCN2A mutant channel mimics adult channel properties. J Gen Physiol. 2020; 152: e201912468. 32291436 PMC7201879
  58. [61]Thompson CH, Ben‐Shalom R, Bender KJ, George AL. Alternative splicing potentiates dysfunction of early‐onset epileptic encephalopathy SCN2A variants. J Gen Physiol. 2020; 152: e201912442. 31995133 PMC7054859
  59. [62]Kang SK, Hawkins NA, Kearney JA. C57BL/6J and C57BL/6N substrains differentially influence phenotype severity in the Scn1a +/− mouse model of Dravet syndrome. Epilepsia Open. 2019; 4: 164– 169. 30868126 PMC6398090
  60. [63]Copping N, Adhikari A, Petkova S, Silverman J. Genetic backgrounds have unique seizure response profiles and behavioral outcomes following Convulsant administration. Epilepsy Behav. 2019; EB 101: 106547. PMC6901115 31698263
  61. [64]MacDonald BT, Adamska M, Meisler MH. Hypomorphic expression of Dkk1 in the doubleridge mouse: dose dependence and compensatory interactions with Lrp6. Development. 2004; 131: 2543– 2552. 15115753
  62. [65]Calhoun JD, Hawkins NA, Zachwieja NJ, Kearney JA. Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage‐gated sodium channel Scn2a. Epilepsia. 2016; 57: e103– e107. 27112236 PMC4985168
  63. [66]Hawkins NA, Kearney JA. Hlf is a genetic modifier of epilepsy caused by voltage‐gated sodium channel mutations. Epilepsy Res. 2016; 119: 20– 23. 26656780 PMC4698075
  64. [67]Passi GR, Mohammad SS. Dominant SCN2A mutation with variable phenotype in two generations. Brain Dev. 2021; 43: 166– 169. 32893078
  65. [68]Kearney JA, Yang Y, Beyer B, Bergren SK, Claes L, DeJonghe P, et al. Severe epilepsy resulting from genetic interaction between Scn2a and Kcnq2. Hum Mol Genet. 2006; 15: 1043– 1048. 16464983
  66. [69]Aiba I, Noebels JL. Kcnq2/Kv7.2 controls the threshold and bi‐hemispheric symmetry of cortical spreading depolarization. Brain. 2021; 144: 2863– 2878. 33768249 PMC8536937
  67. [70]Indumathy J, Pruitt A, Gautier NM, Crane K, Glasscock E. Kv1.1 deficiency alters repetitive and social behaviors in mice and rescues autistic‐like behaviors due to Scn2a haploinsufficiency. Brain Behav. 2021; 11: e02041. 33484493 PMC8035482
  68. [71]Mishra V, Karumuri BK, Gautier NM, Liu R, Hutson TN, Vanhoof‐Villalba SL, et al. Scn2a deletion improves survival and brain–heart dynamics in the Kcna1‐null mouse model of sudden unexpected death in epilepsy (SUDEP). Hum Mol Genet. 2017; 26: 2091– 2103. 28334922 PMC6075631
  69. [72]Wang H‐G, Bavley CC, Li A, Jones RM, Hackett JE, Bayleyen Y, et al. Scn2a severe hypomorphic mutation decreases excitatory synaptic input and causes autism‐associated behaviors. JCI Insight. 2021; 6(15): e150698. 10.1172/jci.insight.150698 34156984 PMC8410058 · DOI
  70. [73]Middleton SJ, Kneller EM, Chen S, Ogiwara I, Montal M, Yamakawa K, et al. Altered hippocampal replay is associated with memory impairment in mice heterozygous for the Scn2a gene. Nat Neurosci. 2018; 21: 996– 1003. 29867081 PMC7306226
  71. [74]Tatsukawa T, Raveau M, Ogiwara I, Hattori S, Miyamoto H, Mazaki E, et al. Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity. Mol Autism. 2019; 10: 15. 30962870 PMC6437867
  72. [75]Marcantonio W, Simonti M, Léna I, Mantegazza M. Gender‐specific behavioral features of juvenile and adult haplo insufficient Scn2a+/− female mice, model of autism Spectrum disorder. 2023. 10.1101/2023.12.11.571165 PMC12399408 40887751 · DOI
  73. [76]Ma Z, Eaton M, Liu Y, Zhang J, Chen X, Tu X, et al. Deficiency of autism‐related Scn2a gene in mice disrupts sleep patterns and circadian rhythms. Neurobiol Dis. 2022; 168: 105690. 35301122 PMC9018617
  74. [77]Suzuki T, Hattori S, Mizukami H, Nakajima R, Hibi Y, Kato S, et al. Inversed effects of Nav1.2 deficiency at medial prefrontal cortex and ventral tegmental area for Prepulse inhibition in acoustic startle response. Mol Neurobiol. 2023; 61: 622– 634. 10.1007/s12035-023-03610-6 37650965 · DOI
  75. [78]Echevarria‐Cooper DM, Kearney JA. Evaluating the interplay between estrous cyclicity and flurothyl‐induced seizure susceptibility in Scn2a K1422E mice. MicroPublication Biol. 2023. 10.17912/micropub.biology.000850 PMC10757737 38162411 · DOI
  76. [79]Capri KM, Maroni MJ, Deane HV, Concepcion HA, DeCourcey H, Logan RW, et al. Male C57BL6/N and C57BL6/J mice respond differently to constant light and running‐wheel access. Front Behav Neurosci. 2019; 13: 268. 31920578 PMC6914853
  77. [80]Tamura S, Nelson AD, Spratt PW, Kyoung H, Zhou X, Li Z, et al. CRISPR activation rescues abnormalities in SCN2A haploinsufficiency‐associated autism spectrum disorder. 2022. 10.1101/2022.03.30.486483 · DOI
  78. [81]Wagner M, Berecki G, Fazeli W, Nussbaum C, Flemmer AW, Frizzo S, et al. Antisense oligonucleotide treatment in a preterm infant with early‐onset SCN2A developmental and epileptic encephalopathy. Nat Med. 2025; 31: 1– 5. 10.1038/s41591-025-03656-0 40263630 PMC12283366 · DOI
  79. [82]Lauffer MC, van Roon‐Mom W, Aartsma‐Rus A. Possibilities and limitations of antisense oligonucleotide therapies for the treatment of monogenic disorders. Commun Med. 2024; 4: 1– 11. 38182878 PMC10770028
  80. [83]Anderson LL, Thompson CH, Hawkins NA, Nath RD, Petersohn AA, Rajamani S, et al. Antiepileptic activity of preferential inhibitors of persistent sodium current. Epilepsia. 2014; 55: 1274– 1283. 24862204 PMC4126848
  81. [84]Comba R, Gervais N, Mumby D, Holahan M. Emergence of spatial behavioral function and associated mossy fiber connectivity and c‐Fos labeling patterns in the hippocampus of rats. F1000Res. 2015; 4: 396. 26925223 PMC4712777
  82. [86]Kim Y, Hsu C‐L, Cembrowski MS, Mensh BD, Spruston N. Dendritic sodium spikes are required for long‐term potentiation at distal synapses on hippocampal pyramidal neurons. elife. 2015; 4: e06414. 26247712 PMC4576155
  83. [87]Oyrer J, Maljevic S, Scheffer IE, Berkovic SF, Petrou S, Reid CA. Ion channels in genetic epilepsy: from genes and mechanisms to disease‐targeted therapies. Pharmacol Rev. 2018; 70: 142– 173. 29263209 PMC5738717
  84. [88]Reynolds C, King MD, Gorman KM. The phenotypic spectrum of SCN2A‐related epilepsy. Eur J Paediatr Neurol. 2020; 24: 117– 122. 31924505
  85. [89]Kile KB, Tian N, Durand DM. Low frequency stimulation decreases seizure activity in a mutation model of epilepsy. Epilepsia. 2010; 51: 1745– 1753. 20659150 PMC3569726
  86. [90]Mithani K, Breitbart S, Fasano A, Gorodetsky C, Ibrahim GM. Deep brain stimulation for status dystonicus in a toddler with SCN2A‐related disorder. Childs Nerv Syst. 2023; 39: 3033– 3035. 37642686
  87. [91]Gong B, Rhodes KJ, Bekele‐Arcuri Z, Trimmer JS. Type I and type II Na(+) channel alpha‐subunit polypeptides exhibit distinct spatial and temporal patterning, and association with auxiliary subunits in rat brain. J Comp Neurol. 1999; 412: 342– 352. 10441760
  88. [92]Westenbroek RE, Merrick DK, Catterall WA. Differential subcellular localization of the RI and RII Na+ channel subtypes in central neurons. Neuron. 1989; 3: 695– 704. 2561976
  89. [93]Kastner DB, Williams G, Holobetz C, Romano JP, Dayan P. The choice‐wide behavioral association study: data‐driven idenootification of interpretable behavioral components. 2024. 10.1101/2024.02.26.582115 PMC13572513 42733062 · DOI
  90. [94]Spratt PWE. (2020). Sodium channel dysfunction in autism spectrum disorder. [Doctroal Dissertation, UCSF]. ProQuest ID: Spratt_ucsf_0034D_11983. Merritt ID: ark:/13030/m5r54z4t. Available from: https://escholarship.org/uc/item/4nz251dr
  91. [95]Misra SN, Kahlig KM, George AL. Impaired NaV1.2 function and reduced cell surface expression in benign familial neonatal‐infantile seizures. Epilepsia. 2008; 49: 1535– 1545. 18479388 PMC3647030
  92. [96]Zeng Q, Yang Y, Duan J, Niu X, Chen Y, Wang D, et al. SCN2A‐related epilepsy: the phenotypic Spectrum, treatment and prognosis. Front Mol Neurosci. 2022; 15: 809951. 35431799 PMC9005871
  93. [98]Thompson CH, Potet F, Abramova TV, DeKeyser JM, Ghabra NF, Vanoye CG, et al. Epilepsy‐associated SCN2A (NaV1.2) variants exhibit diverse and complex functional properties. J Gen Physiol. 2023; 155: e202313375. 37578743 PMC10424433

Cited by

Sorted by citations

Authors
Scott, K. E. J., Hermosillo Arrieta, M. F., & Williams, A. J.
Affiliations
  • University of Iowa (US)
  • Iowa Neuroscience Institute University of Iowa Iowa City Iowa USA
Corresponding author
Williams, Aislinn J.
ORCID
Venue
Epilepsia
Publisher
Wiley
Published
2025-08-30
Volume
66
Issue
12
Pages
4624-4638
ISSN
  • 0013-9580 (ISSN-L)
  • 1528-1167
DOI
10.1111/epi.18615
PMC
PMC12779317
OpenAlex
W4413852499
Cited by
9
References
5
Citations by year
2026: 8 · 2025: 1
FWCI
1.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Epilepsia (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
Funders
  • National Institute of Neurological Disorders and Stroke (R25 NS130966, T32 NS007421)
  • U.S. Department of Defense (DOD AR220030)
  • Roy J. and Lucille A. Carver College of Medicine, University of Iowa (Roy J. Carver Trust)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • 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
Keywords
SCN2A, rodent models, epilepsy, autism spectrum disorder, gain-of-function mutations, loss-of-function mutations, neuronal excitability, seizure phenotype, behavioral phenotypes, learning disabilities, sociability, sensory processing, gene-environment interaction, CRISPR activation, antisense oligonucleotides, deep brain stimulation, developmental stages, sex differences
MeSH terms
Animals, Disease Models, Animal, Epilepsy, Humans, Mice, 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.

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