Affinage

SCN1A

Sodium channel protein type 1 subunit alpha · UniProt P35498

Length
2009 aa
Mass
229.0 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SCN1A encodes Nav1.1, a voltage-gated sodium channel alpha subunit whose function is most critical in GABAergic inhibitory interneurons, where its loss selectively impairs sodium currents and action potential firing without affecting excitatory pyramidal neurons, producing network disinhibition and epilepsy (PMID:20194124, PMID:27458797, PMID:33658306). Nav1.1 localizes to nodes of Ranvier and to a proximal axon initial segment subcompartment, positioning it to control action potential generation and propagation (PMID:18621130). The dominant disease mechanism is haploinsufficiency: truncating Dravet-syndrome mutations are not dominant-negative and do not impair co-expressed wild-type channels (PMID:22150645), and many missense variants cause loss of function either by reduced channel activity or by folding/trafficking defects that lower cell surface expression, with some defective mutants rescuable by pharmacological chaperones such as phenytoin or by ER-targeted interactions (PMID:17054685, PMID:23086956, PMID:25576396). A distinct subset of variants instead causes gain of function—through increased persistent (late) sodium current or shifted gating—linked to epilepsy and familial hemiplegic migraine type 3; paradoxically, some gain-of-function variants drive interneurons into depolarization block, producing a 'functional dominant-negative' disinhibition more severe than haploinsufficiency (PMID:23398611, PMID:30779207, PMID:35696452, PMID:34755109). At the circuit level, Nav1.1 in parvalbumin-positive and fast-spiking interneurons sustains their excitability, gamma/theta oscillations, and GABA release, and its disruption impairs spatial memory and working memory (PMID:34843701, PMID:29551491, PMID:32377688, PMID:26978272). Nav1.1 abundance is controlled post-translationally by neddylation, which stabilizes the protein in parvalbumin interneurons (PMID:33651714), and post-transcriptionally by MDH2 binding to the SCN1A 3' UTR under oxidative/seizure conditions to reduce its expression (PMID:28433711); transcription depends on the 1b alternative start-site regulatory element (PMID:33910599). Because haploinsufficiency is the core defect, restoring Nav1.1 expression—via TANGO antisense oligonucleotides, dCas9 transcriptional activation, conditional gene re-activation, or interneuron-specific AAV gene delivery—rescues interneuron firing and seizures, with the safety requirement that expression be confined to interneurons (PMID:34843701, PMID:32848094, PMID:31607539, PMID:35013317, PMID:40106582).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 2006 High

    Establishing whether SMEI-associated SCN1A mutations actually disrupt channel function showed that most produce complete or severe loss of sodium current, defining the molecular basis of the disease.

    Evidence Whole-cell patch clamp of multiple recombinant human SCN1A mutants in tsA201 cells with beta subunits

    PMID:17054685

    Open questions at the time
    • Heterologous cells do not reproduce neuronal context
    • Did not address which neuron types are selectively affected
  2. 2005 High

    Linking a single loss-of-function variant to a clinical phenotype through co-segregation tied SCN1A biophysical defects to inherited febrile seizures.

    Evidence Patch-clamp activation analysis of M145T plus co-segregation in an Italian family

    PMID:16326807

    Open questions at the time
    • Single variant
    • Circuit-level consequence not measured
  3. 2008 Medium

    Defining where Nav1.1 sits subcellularly placed the channel at nodes of Ranvier and the axon initial segment, framing its role in action potential generation and propagation.

    Evidence Immunohistochemistry and subcellular localization across adult mouse CNS

    PMID:18621130

    Open questions at the time
    • Does not assign function to specific neuron classes
    • Antibody-based localization without functional correlate
  4. 2010 High

    Resolving why loss of a broadly important channel causes hyperexcitability showed that the deficit is selective to GABAergic inhibitory neurons, explaining disinhibition as the core circuit mechanism.

    Evidence Patch clamp of inhibitory vs excitatory hippocampal and cerebellar neurons in Scn1a mutant mice

    PMID:20194124

    Open questions at the time
    • Mechanism of cell-type selectivity not fully explained
    • Did not distinguish interneuron subclasses
  5. 2011 High

    Determining whether truncating mutations poison wild-type channels established that Dravet syndrome arises from pure haploinsufficiency rather than dominant-negative interference.

    Evidence Co-expression of truncated mutants with WT Nav channels in tsA-201 cells plus Nav1.1 KO neuron recordings

    PMID:22150645

    Open questions at the time
    • Modest Nav1.6 gating effects left unexplained
    • Missense mechanisms not addressed
  6. 2012 High

    Confirming haploinsufficiency in a human-derived system and that interneuron deficits are restorable, iPSC modeling showed inhibitory-neuron-specific defects rescued by a Nav1.1 transgene.

    Evidence iPSC-derived MGE-like inhibitory vs excitatory neurons, patch clamp, transgene rescue

    PMID:27458797

    Open questions at the time
    • In vitro neurons lack mature circuit context
    • Single mutation tested
  7. 2012 High

    Identifying trafficking defects as a loss-of-function route and showing pharmacological chaperone rescue opened a mechanistic and therapeutic axis distinct from gating defects.

    Evidence Surface expression assays and patch clamp with phenytoin/lamotrigine/VRT-325 in heterologous cells

    PMID:23086956

    Open questions at the time
    • Surface rescue did not always restore function
    • Not validated in neurons
  8. 2015 Medium

    Demonstrating that ER-based interactions suffice for rescue and that rescued epileptogenic mutants stay loss-of-function while FHM mutants stay gain-of-function clarified the divergent pathophysiology of folding-defective variants.

    Evidence Heterologous expression with low temperature, chaperones, and ER-targeted scorpion toxin rescue plus patch clamp

    PMID:25576396

    Open questions at the time
    • Single lab
    • Therapeutic translatability of ER-targeted rescue untested in vivo
  9. 2013 Medium

    Explaining how one variant can yield both epilepsy and migraine, T1174S showed condition-dependent switching between net loss and gain of function.

    Evidence Patch clamp with cytoplasmic dialysis, computational modeling, and clinical genetics

    PMID:23398611

    Open questions at the time
    • Switching mechanism (modulatory factor) not identified
    • Single family
  10. 2018 Medium

    Establishing a second FHM-3 variant where a folding defect masks an underlying gain of function consolidated the FHM-3 mechanistic model.

    Evidence Heterologous expression and patch clamp of L1670W after low-temperature/neuronal rescue

    PMID:30038559

    Open questions at the time
    • Single variant
    • In vivo migraine relevance not tested
  11. 2019 High

    Showing that a biophysical gain-of-function variant can paradoxically worsen disinhibition by driving interneurons into depolarization block reconciled severe phenotypes with gain-of-function gating.

    Evidence Patch clamp of T226M, dynamic action potential clamp, and computational neuron modeling

    PMID:30779207

    Open questions at the time
    • Depolarization-block model not directly confirmed in vivo for this variant
    • Other neuron types not assessed
  12. 2019 Medium

    Quantifying gating changes across many gain-of-function variants linked persistent-current magnitude to action-current amplitude, distinguishing epilepsy from FHM-3 variant severity.

    Evidence Voltage-clamp electrophysiology of multiple variants in mammalian cells, multi-center

    PMID:35696452

    Open questions at the time
    • Heterologous readout, not neuronal network
    • Genotype-phenotype correlation incomplete
  13. 2019 High

    Identifying the cell type whose excitability fails—parvalbumin interneurons—and rescuing it with TANGO ASO connected molecular deficit to a tractable therapy.

    Evidence Patch clamp of PV interneurons in Scn1a+/- slices, STK-001 ASO treatment, seizure monitoring

    PMID:34843701

    Open questions at the time
    • Long-term durability not addressed here
    • Other interneuron classes not tested
  14. 2019 Medium

    Revealing that some inhibitory neurons become MORE excitable after Nav1.1 loss (reticular thalamic via SK channel downregulation) refined the view that disinhibition is not uniform across inhibitory cells.

    Evidence Electrophysiology of RT neurons in DS mice, SK channel expression analysis, seizure monitoring

    PMID:30605686

    Open questions at the time
    • Mechanism of SK downregulation unclear
    • Single lab
  15. 2019 High

    Proving haploinsufficiency is the primary pathogenic event, dCas9 activation of endogenous Scn1a restored interneuron firing and attenuated seizures in vivo.

    Evidence CRISPR-dCas9 activation, AAV delivery, PV interneuron patch clamp, febrile seizure assay

    PMID:31607539

    Open questions at the time
    • Activation specificity and chronic effects not fully characterized
    • Febrile-only seizure readout
  16. 2017 Medium

    Discovering MDH2 as a 3'UTR-binding regulator that lowers Nav1.1 under oxidative/seizure conditions identified a post-transcriptional control point coupling redox state to channel abundance.

    Evidence RNA-binding identification, reporter assays in HEK-293, MDH2 knockdown/overexpression, seizure-mouse tissue, ROS manipulation

    PMID:28433711

    Open questions at the time
    • Direct binding site not mapped at nucleotide resolution
    • Physiological significance in interneurons untested
  17. 2018 High

    Establishing Nav1.1 as causal for interneuron action-potential kinetics and gamma oscillations through bidirectional manipulation generalized its role to cognition and even Alzheimer's-model circuits.

    Evidence Interneuron transplants with Nav1.1 overexpression/knockdown, EEG, behavior, patch clamp of transplanted cells

    PMID:29551491

    Open questions at the time
    • Mechanism of oscillatory enhancement at molecular level not detailed
    • Transplant model differs from endogenous disease
  18. 2016 Medium

    Localized knockdown showed Nav1.1 sustains interneuron firing, theta/gamma coupling, and theta phase precession underlying spatial memory.

    Evidence Hippocampal shRNA knockdown, in vivo recording of interneurons vs pyramidal cells, place-cell and behavioral analysis

    PMID:32377688

    Open questions at the time
    • Knockdown efficiency/specificity constraints
    • Single lab
  19. 2016 Medium

    Demonstrating that medial septal Nav1.1 supports fast/burst firing and theta phase-locking extended its circuit role to working memory.

    Evidence RNA interference knockdown in medial septum, in vivo electrophysiology, theta analysis during working-memory task

    PMID:26978272

    Open questions at the time
    • Cell-type identity of affected septal neurons not fully resolved
    • Single lab
  20. 2018 Medium

    Showing extracellular acidosis shifts Nav1.1 activation and reduces current density identified an environmental modulator of channel availability.

    Evidence Patch clamp at varying extracellular pH in heterologous cells

    PMID:30362397

    Open questions at the time
    • Physiological/seizure relevance untested
    • Single method
  21. 2021 Medium

    Defining the 1b alternative start-site as a critical regulatory element explained a transcriptional route to Nav1.1 deficiency and seizures.

    Evidence Transgenic deletion of the 1b interval, mRNA/protein quantification, EEG and behavioral testing

    PMID:33910599

    Open questions at the time
    • Trans-acting factors at 1b not identified
    • Single lab
  22. 2021 High

    Identifying neddylation as a stabilizer of Nav1.1 in parvalbumin interneurons revealed a post-translational control point whose loss alone causes epilepsy.

    Evidence Conditional Nae1 KO in PVINs, patch clamp, proteomics, immunohistochemistry, seizure monitoring

    PMID:33651714

    Open questions at the time
    • Direct neddylation site on Nav1.1 not mapped
    • Whether neddylation modulates other Nav subtypes unclear
  23. 2021 Medium

    Characterizing additional gain-of-function variants (R1636Q, A1685S, T782I, K1270T) tied persistent-current increases and interneuron-specific excitability deficits to severe phenotypes and showed pharmacological correctability.

    Evidence Patch clamp in HEK cells with beta subunits, computational modeling, oxcarbazepine testing, and CRISPR knock-in PV interneuron recordings

    PMID:33658306 PMID:34755109 PMID:36287100

    Open questions at the time
    • Heterologous and single-variant studies limit generalization
    • In vivo therapeutic effect of channel block not established
  24. 2014 Medium

    Comparing homologous pore mutations across paralogs established that SCN1A pore variants are more functionally severe than equivalent SCN3A mutations.

    Evidence Comparative patch clamp of homologous Nav1.1 and Nav1.3 mutations

    PMID:24990319

    Open questions at the time
    • Structural basis of differential sensitivity not resolved
    • Single lab
  25. 2024 Medium

    Systematically testing splicing impact of variants distinguished true splice-affecting changes from benign intronic ones and showed Nav1.1 intolerance to structural variation, refining variant interpretation.

    Evidence Minigene splicing reporter covering all 26 exons, 95 variants tested, genotype-phenotype correlation

    PMID:37956038

    Open questions at the time
    • Reporter context may not capture endogenous splicing fully
    • Functional protein-level confirmation not performed for all variants
  26. 2022 High

    Showing that gene re-activation after symptom onset—even in adults—rescues seizures, behavior, and interneuron firing established that the disease state is reversible and not developmentally locked.

    Evidence Conditional Scn1a knock-in with inducible re-activation, EEG, interneuron patch clamp, behavior, RNA-seq

    PMID:35013317

    Open questions at the time
    • Idealized re-activation differs from achievable clinical delivery
    • Durability beyond study window not addressed
  27. 2025 High

    Delivering SCN1A under an interneuron-specific enhancer via dual-AAV produced functional Nav1.1 and protected DS mice, while pan-neuronal expression was harmful—establishing cell-type-restricted expression as a therapeutic requirement.

    Evidence Split-intein dual-AAV with DLX2.0 enhancer vs SYNAPSIN I promoter, western blot, HEK patch clamp, immunohistochemistry, seizure/survival in DS mice

    PMID:40106582

    Open questions at the time
    • Long-term safety and durability in larger species untested
    • Optimal dosing window not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How Nav1.1's molecular features (neddylation sites, MDH2 binding determinants, structural domains) mechanistically confer interneuron-selective dependence remains unresolved.
  • No mapped neddylation residue on Nav1.1
  • MDH2 binding site not defined at nucleotide resolution
  • Molecular basis of interneuron-selective requirement unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4
Localization
GO:0005886 plasma membrane 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-1643685 Disease 3
Partners
MDH2NAE1

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 Loss-of-function mutations in NaV1.1 (SCN1A) cause severely impaired sodium currents and action potential firing specifically in hippocampal GABAergic inhibitory neurons without detectable effect on excitatory pyramidal neurons, leading to network hyperexcitability. Similarly, sodium currents and action potential firing are impaired in GABAergic Purkinje neurons of the cerebellum. Electrophysiological recording (patch clamp) in mouse models with loss-of-function Scn1a mutations; comparison of inhibitory vs. excitatory neuron firing The Journal of physiology High 20194124
2006 Multiple SMEI-associated missense SCN1A mutations (G177E, I227S, R393H, Y426N, H939Q, C959R, delF1289, T1909I) result in either complete loss of function or significantly reduced sodium channel activity when expressed in heterologous cells. Six of eight tested mutations were completely nonfunctional; Y426N showed decreased channel availability and T1909I showed increased persistent sodium current. Whole-cell patch-clamp recording of recombinant human SCN1A mutants expressed in tsA201 cells with beta1 and beta2 accessory subunits Epilepsia High 17054685
2005 The M145T SCN1A mutation in the first transmembrane segment of domain I causes a 60% reduction of current density and a 10-mV positive shift of the activation curve (loss-of-function) in mammalian cells, co-segregating with familial simple febrile seizures. Functional studies (patch-clamp electrophysiology) in mammalian cells expressing mutant Nav1.1; co-segregation analysis in a large Italian family Proceedings of the National Academy of Sciences of the United States of America High 16326807
2008 Nav1.1 is predominantly expressed in nodes of Ranvier throughout the adult CNS (spinal cord and brain regions) and concentrated in a proximal axon initial segment (AIS) subcompartment in spinal cord neurons including 80% of motor neurons, suggesting a role in control of action potential generation and propagation. Immunohistochemistry and direct subcellular localization experiments in adult mouse CNS tissue Molecular and cellular neurosciences Medium 18621130
2011 SCN1A truncating mutations causing Dravet syndrome result in pure haploinsufficiency: truncated Nav1.1 mutants (R222* and R1234*) are not dominant negative and do not impair expression or function of co-expressed wild-type Nav1.1, Nav1.2, or Nav1.3 channels. Some gating properties of Nav1.6 were modestly affected by co-expression but recordings from Nav1.1 KO mouse hippocampal neurons showed no significant modification. Whole-cell patch clamp of tsA-201 cells co-transfected with truncated mutants and wild-type channels; electrophysiology of hippocampal neurons from Nav1.1 KO mice Epilepsia High 22150645
2012 The Nav1.1 p.S1328P mutation (Dravet syndrome) causes decreased sodium current amplitude and hypersensitivity to steady-state inactivation in iPSC-derived neurons. Dravet MGE-like inhibitory neurons showed deficits in sodium currents and action potential firing that were rescued by a Nav1.1 transgene, whereas Dravet excitatory neurons were functionally normal. iPSC differentiation into telencephalic excitatory or MGE-like inhibitory neurons; patch-clamp electrophysiology; rescue by Nav1.1 transgene eLife High 27458797
2012 Several nontruncating SCN1A missense and in-frame deletion mutations (L986F, delF1289, R1648C, F1661S, G1674R, G1979E) associated with SMEI exhibit reduced cell surface expression consistent with impaired trafficking to the plasma membrane. Phenytoin increased cell surface expression of wild-type and two mutant channels; lamotrigine selectively increased surface expression of R1648C. Rescue of G1674R to the plasma membrane did not restore channel function, indicating an additional intrinsic functional defect. Cell surface expression assays and patch-clamp electrophysiology in heterologous cells; pharmacological chaperone treatment with phenytoin, lamotrigine, and VRT-325 The Journal of biological chemistry High 23086956
2013 The T1174S SCN1A mutation exhibits divergent functional effects: a positive shift of the activation curve and deceleration of recovery from fast inactivation (loss of function), and an increase of persistent sodium current (gain of function) that was abolished by cytoplasmic dialysis, indicating modulation-dependent switching. Computational modeling showed T1174S can produce either net loss or gain of function depending on conditions, consistent with a family exhibiting both epilepsy and familial hemiplegic migraine phenotypes. Whole-cell patch-clamp electrophysiology in tsA-201 cells; computational neuron modeling; clinical genetic analysis Epilepsia Medium 23398611
2015 Several epileptogenic Nav1.1 missense mutations exhibit folding defects with reduced cell surface expression (loss of function). Four mutations were rescuable by low temperature, co-expression with different proteins, or the pharmacological chaperone phenytoin. A scorpion toxin (CsEI) targeted to the endoplasmic reticulum was able to rescue four mutants, demonstrating that ER-based interactions are sufficient for rescue. Rescued epileptogenic mutants retained overall loss of function, in contrast to rescued FHM-III mutants which showed gain of function. Heterologous expression in cells; cell surface expression assays; patch-clamp electrophysiology under various rescue conditions including low temperature, pharmacological chaperones, and ER-targeted toxin Neurobiology of disease Medium 25576396
2018 The SCN1A L1670W mutation associated with familial hemiplegic migraine type 3 (FHM-3) causes folding/trafficking defects; when rescued by low temperature or expression in neurons, modifications of gating properties result in an overall gain of function. This identifies a second FHM-3 mutation with the same pathophysiological mechanism (folding defect masking a gain-of-function gating effect). Heterologous expression; cell surface expression assays; patch-clamp electrophysiology at low temperature and in neurons Frontiers in molecular neuroscience Medium 30038559
2019 The recurrent SCN1A T226M mutation causes gain of function biophysically (hyperpolarizing shifts of activation and inactivation curves, enhanced fast inactivation), but paradoxically causes interneurons to more readily enter depolarization block, resulting in a 'functional dominant negative' effect causing more profound disinhibition than haploinsufficiency, explaining the more severe phenotype compared to typical Dravet syndrome. Whole-cell patch clamp of T226M Nav1.1 expressed in mammalian cells; dynamic action potential clamp hybrid simulation; computational neuron modeling Annals of neurology High 30779207
2019 Gain-of-function SCN1A variants (associated with epilepsy and familial hemiplegic migraine type 3) alter channel gating properties in ways consistent with neuronal hyperexcitability. Epilepsy gain-of-function variants produce a moderate increase in action current amplitude, while FHM-3 variants induce larger effects particularly on persistent current, resulting in larger increases in action current amplitude. Whole-cell voltage-clamp electrophysiological recordings comparing wild-type versus variant Nav1.1 subunits in mammalian cells Brain : a journal of neurology Medium 35696452
2019 SCN1A loss-of-function mutations reduce the intrinsic excitability of parvalbumin-positive (PV) inhibitory interneurons; treatment with antisense oligonucleotide STK-001 (TANGO approach targeting non-productive SCN1A splicing) rescued PV interneuron excitability to wild-type levels and reduced seizures in Scn1a+/- mice. Patch-clamp electrophysiology of PV interneurons in mouse brain slices; ASO treatment; seizure monitoring in Scn1a+/- mouse model Brain research High 34843701
2019 In a Scn1a loss-of-function mouse model of Dravet syndrome, reticular thalamic (RT) neurons exhibit enhanced excitability with abnormally long bursts of firing caused by downregulation of calcium-activated potassium SK channels, promoting non-convulsive seizures. This demonstrates that Nav1.1 loss does not globally reduce all inhibitory neuron excitability. Electrophysiological recording from RT neurons in DS mouse model slices; SK channel expression analysis; seizure monitoring Cell reports Medium 30605686
2021 Neddylation regulates Nav1.1 protein stability in parvalbumin-positive interneurons (PVINs). Deletion of Nae1 (E1 ligase for neddylation) in PVINs reduces Nav1.1 protein levels and sodium current density (without changing channel gating properties), decreases PVIN excitability and GABA release, increases pyramidal neuron network excitability, and causes spontaneous epileptic seizures and premature death in mice. Conditional KO mouse model; patch-clamp electrophysiology; proteomic analysis; immunohistochemistry; seizure monitoring The Journal of clinical investigation High 33651714
2017 MDH2 is an RNA-binding protein that binds to conserved regions in the 3' UTR of SCN1A mRNA and regulates its expression at the posttranscriptional level. Knockdown or inactivation of MDH2 in HEK-293 cells increased SCN1A reporter expression, while MDH2 overexpression decreased it by affecting mRNA stability. In seizure mice, upregulated MDH2 contributed to decreased Nav1.1 levels; seizure-induced H2O2 promoted MDH2 binding to Scn1a 3' UTR, while reducing agents decreased it. RNA-binding protein identification; reporter gene assays in HEK-293 cells; MDH2 knockdown/overexpression; hippocampal tissue analysis from seizure mice; ROS manipulation Biochimica et biophysica acta. Molecular basis of disease Medium 28433711
2020 Antisense oligonucleotides using the TANGO approach (targeting non-productive SCN1A splicing events) increase productive Scn1a transcript and Nav1.1 protein expression in mouse brain. A single intracerebroventricular dose reduced electrographic seizures and SUDEP incidence in Scn1a+/- DS mice. ASO delivery in vivo; Scn1a mRNA and protein quantification by RT-PCR and western blot; EEG seizure monitoring; survival analysis in DS mouse model Science translational medicine High 32848094
2019 dCas9-mediated transcriptional activation of the Scn1a gene using a specific sgRNA increases Scn1a expression and Nav1.1 protein levels in neurons. In Dravet syndrome mouse model, AAV-delivered dCas9-activation system recovered parvalbumin interneuron firing ability and significantly attenuated febrile seizures, demonstrating that Scn1a haploinsufficiency is the primary pathogenic mechanism. CRISPR-dCas9 activation system; sgRNA screening; AAV delivery in vivo; patch-clamp of PV interneurons; febrile seizure induction assay; Nav1.1 protein quantification Molecular therapy : the journal of the American Society of Gene Therapy High 31607539
2022 Scn1a gene re-activation at P30 (after symptom onset) in a conditional knock-in DS mouse model completely rescued both spontaneous and thermally-induced seizures, improved behavioral abnormalities, and normalized hippocampal fast-spiking interneuron firing. Gene re-activation also rescued seizures in adult (P90) DS mice after months of attacks, and normalized astrogliosis-associated gene expression changes. Conditional Scn1a knock-in mouse model with inducible re-activation; EEG seizure monitoring; patch-clamp of hippocampal interneurons; behavioral testing; RNA-seq; immunohistochemistry Nature communications High 35013317
2018 Nav1.1-overexpressing interneuron transplants (from embryonic medial ganglionic eminence) enhance gamma oscillatory activity, reduce network hypersynchrony, and improve cognitive functions in hAPP-transgenic (Alzheimer's model) mice. Increased Nav1.1 levels accelerated action potential kinetics of transplanted fast-spiking and non-fast-spiking interneurons. Nav1.1-deficient interneuron transplants caused behavioral abnormalities in wild-type mice, establishing a causal role for Nav1.1 in interneuron function. Interneuron transplantation with Nav1.1 overexpression or knockdown; in vivo electrophysiology (EEG oscillations); behavioral testing; patch-clamp of transplanted interneurons Neuron High 29551491
2016 Focal knockdown of Nav1.1 in the dorsal hippocampus via shRNA decreases firing rate of inhibitory interneurons (but not pyramidal cells), reduces theta/gamma coupling, impairs theta phase precession in place cells, and impairs spatial novelty recognition behavior. shRNA knockdown; in vivo electrophysiology recording of interneurons and pyramidal cells; hippocampal oscillation analysis; place cell recording; behavioral testing Cerebral cortex (New York, N.Y. : 1991) Medium 32377688
2016 Nav1.1 knockdown in the medial septum impairs fast- and burst-firing properties of neurons in vivo, reduces the proportion of neurons firing phase-locked to hippocampal theta oscillations, disrupts medial septal regulation of theta rhythm, and impairs working memory performance. RNA interference knockdown; in vivo electrophysiology; hippocampal theta oscillation analysis during working memory task PloS one Medium 26978272
2018 Extracellular acidosis causes a depolarizing shift in voltage-dependence of Nav1.1 activation and a moderate reduction in current density, without changing steady-state fast inactivation or recovery from fast inactivation. Whole-cell patch-clamp electrophysiology at varying extracellular pH in heterologous expression system Channels (Austin, Tex.) Medium 30362397
2021 The SCN1A 1b non-coding regulatory region (alternative transcriptional start site) is a critical regulatory element for Scn1a expression. Mice with deletion of the extended 1b interval show severe reductions of Scn1a mRNA and Nav1.1 protein throughout the brain, accompanied by EEG and thermal seizures and behavioral deficits. Transgenic mouse deletion of 1b regulatory region; Scn1a/Nav1.1 mRNA and protein quantification; EEG seizure monitoring; behavioral testing Genome medicine Medium 33910599
2021 The SCN1A p.R1636Q variant causes gain of function through normal current density but a leftward shift of steady-state inactivation and slower inactivation kinetics producing prominent late (persistent) sodium current. Both wild-type and variant channels showed sensitivity to block by oxcarbazepine, which partially corrected the electrophysiological abnormalities. Whole-cell voltage-clamp electrophysiology in HEK-293T cells; co-expression with Nav β1 and β2 subunits; pharmacological testing with oxcarbazepine Epilepsia Medium 36287100
2021 Two SCN1A gain-of-function variants (p.A1685S and p.T782I, the latter mosaic) both produce gain-of-function effects in heterologous expression. p.T782I produces a severe persistent sodium current; computational modeling showed large persistent sodium currents induce hyper-excitability in cortical neuron models, relating severe DEE phenotype to quantified channel dysfunction. Whole-cell patch clamp in heterologous expression system; computational modeling of cortical neurons Brain communications Medium 34755109
2007 Nav1.1 is expressed in retinal AII amacrine cells at the inner nuclear layer/inner plexiform layer border, in addition to retinal ganglion cells, as demonstrated by combining in situ hybridization with parvalbumin immunohistochemistry. In situ hybridization combined with immunohistochemistry in rat retina Neuroscience letters Low 17709186
2014 Pore region SCN1A mutations cause complete loss of sodium channel function, whereas the homologous pore mutation in SCN3A (N302S vs N301S) only slightly reduces channel activity, demonstrating that SCN1A pore mutations have a more severe impact on channel function than equivalent SCN3A mutations. Whole-cell patch-clamp electrophysiology comparing homologous mutations in Nav1.1 (N301S) and Nav1.3 (N302S) expressed in heterologous cells Molecular neurobiology Medium 24990319
2024 Functional analysis using a splicing reporter system (18 vectors covering all 26 SCN1A coding exons) showed that approximately 20% of reported intronic SCN1A variants outside canonical splice sites had no influence on splicing. The majority of predicted exonic splice-affecting variants confirmed to affect splicing, revealing their true molecular mechanism. The Nav1.1 protein is highly intolerant to structural variations (no phenotype difference between in-frame and out-of-frame isoforms). Minigene/splicing reporter assay system covering all 26 SCN1A exons; functional testing of 95 variants; genotype-phenotype correlation Brain : a journal of neurology Medium 37956038
2025 A split-intein dual-AAV approach delivering SCN1A driven by an interneuron-specific DLX2.0 enhancer produces full-length Nav1.1 protein and functional sodium channels in vitro. In vivo administration in DS mouse models conferred strong protection against mortality and seizures in an interneuron-specific and dose-dependent manner. Expression of SCN1A in all neurons (SYNAPSIN I promoter) caused increased preweaning mortality, demonstrating that interneuron-specific expression is required for therapeutic safety. Split-intein dual-AAV vector construction; Western blot; patch-clamp in HEK293 cells; immunohistochemistry in mouse brain; seizure monitoring and survival analysis in DS mouse models Science translational medicine High 40106582
2021 Parvalbumin interneurons carrying the K1270T SCN1A GEFS+ mutation show a depolarized shift in action potential threshold and reduced action potential amplitude in CA1 hippocampal slices, while excitatory CA1 pyramidal neurons are unaffected, demonstrating a constitutive interneuron-specific excitability deficit. CRISPR/Cas9 knock-in of K1270T mutation in mice; current-clamp recording from PV interneurons and pyramidal neurons in acute hippocampal slices eNeuro Medium 33658306

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain : a journal of neurology 387 17347258
2010 NaV1.1 channels and epilepsy. The Journal of physiology 341 20194124
2010 Sodium channel SCN1A and epilepsy: mutations and mechanisms. Epilepsia 288 20831750
2008 Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. Journal of medical genetics 283 18930999
2005 SCN1A mutations and epilepsy. Human mutation 267 15880351
2020 Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome. Science translational medicine 261 32848094
2003 Sodium channels SCN1A, SCN2A and SCN3A in familial autism. Molecular psychiatry 229 12610651
2011 Genotype-phenotype associations in SCN1A-related epilepsies. Neurology 203 21248271
2003 Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy. Neurology 200 12821740
2018 Nav1.1-Overexpressing Interneuron Transplants Restore Brain Rhythms and Cognition in a Mouse Model of Alzheimer's Disease. Neuron 187 29551491
2019 dCas9-Based Scn1a Gene Activation Restores Inhibitory Interneuron Excitability and Attenuates Seizures in Dravet Syndrome Mice. Molecular therapy : the journal of the American Society of Gene Therapy 175 31607539
2015 The SCN1A mutation database: updating information and analysis of the relationships among genotype, functional alteration, and phenotype. Human mutation 158 25754450
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2013 The SCN1A gene variants and epileptic encephalopathies. Journal of human genetics 68 23884151
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2022 Development and Validation of a Prediction Model for Early Diagnosis of SCN1A-Related Epilepsies. Neurology 60 35074891
2019 SCN1A/NaV 1.1 channelopathies: Mechanisms in expression systems, animal models, and human iPSC models. Epilepsia 60 31904127
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2013 Divergent effects of the T1174S SCN1A mutation associated with seizures and hemiplegic migraine. Epilepsia 54 23398611
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2013 SCN1A, SCN2A and SCN3A gene polymorphisms and responsiveness to antiepileptic drugs: a multicenter cohort study and meta-analysis. Pharmacogenomics 52 23859570
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