Table 5.
Animal models of SCN1A/SCN1B-associated epilepsies
| Genetic defect | Phenotype | Human syndrome | References | |
|---|---|---|---|---|
| Mouse models | ||||
| SCN1A KO | Deletion of last exon (domain IV, S3–S6 segment and carboxyl terminus) | Heterozygous: thermally induced myoclonic and generalized seizures (PN20–22, PN30–46); spontaneous seizures (>PN32); interictal spikes at normal temperature (PN30–46) | Dravet | Yu et al. 2006; Kalume et al. 2007; Oakley et al. 2009; Kalume et al. 2013 |
| SCN1A CKO | Exon 25 deletion, in forebrain GABAergic interneurons | Selective loss of Nav1.1 in forebrain cortical and hippocampal GABAergic neurons; spontaneous seizures (stages 3–5, Racine scale); premature death after seizures (PN18–22); thermally induced seizures (PN22) | Dravet | Cheah et al. 2012 |
| SCN1A KI, R1407X | R1407X nonsense mutation | Heterozygous: low threshold in pentylenetetrazole seizures; QT prolongation, ectopic ventricular foci, idioventricular rhythms, beat-to-beat variability, ventricular fibrillation, focal bradycardia; 23% mortality Heterozygous and homozygous: spontaneous seizures in first postnatal month Cardiac myocytes, heterozygous: increased excitability, action potential duration | Dravet | Ogiwara et al. 2007; Auerbach et al. 2013 |
| SCN1A CKO | Conditional deletion of exon 7 | Deletion in global inhibitory neurons: heterozygous develop spontaneous seizures (PN16) with occasional subsequent death. Homozygous: PN10–15: hypoactivity, jerks; death by PN15 Deletion in forebrain excitatory neurons: no spontaneous seizures Deletion in forebrain excitatory neurons and haploinsufficiency in inhibitory neurons: ameliorates seizure-related sudden death Deletion in parvalbumin interneurons: homozygotes Ataxia and spontaneous seizures and ataxia (PN10 and PN14, respectively; death by PN30) Heterozygotes: spontaneous seizures and death after PN16 |
Dravet | Ogiwara et al. 2013 |
| BAC transgene with R1648H mutation | R1648H mutation | More severe kainic acid seizures Cortical interneurons with slower recovery from inactivation and increased use-dependent inactivation of sodium channels | GEFS+ | Tang et al. 2009 |
| SCN1A KI, R1648H | Human R1648H mutation | Homozygous: spontaneous generalized seizures (jump, jerks, head nodding, clonus, hindlimb extension); lower thresholds to hyperthermic or flurothyl seizures; premature death PN16–26; cortical interneurons with reduced firing, slower recovery from inactivation, and increased use-dependent inactivation of sodium channels Heterozygous: less severe phenotype than homozygous | GEFS+ | Martin et al. 2010 |
| SCN1B KO | SCN1B deletion (both β1 and β1A isoforms) | Homozygous: ataxia, spontaneous seizures, early mortality | Dravet | Chen et al. 2004 |
| SCN1B KI, C121W | Human C121W SCN1B mutation | Homozygous: tremor, jerks, hunched back, poor weight gain, early mortality; spontaneous seizures (stages 1–6, Racine scale); thermal seizures; seizures respond to diazepam, stiripentol, but not to lamotrigine; thermal seizures respond to retigabine; increased excitability of layer 2/3 pyramidal neurons, but no change in CA1 or layer 5 pyramidal neurons; no change in GABAergic IPSCs in subicular neurons; reduced arborization of neurons | Dravet | Reid et al. 2014 |
| Other animal models | ||||
| Scn1Lab (zebrafish) | Met to Arg mutation in domain III | In vivo: increased swim activity, unprovoked whole body convulsions, and rapid undirected movements Extracellular field recordings in agar immobilized larvae: seizure patterns; hyperthermia-induced seizures | Dravet | Baraban et al. 2013 |
| SCN1A KI, S1231R (Drosophila) | S1231R mutation | Spontaneous and thermal seizures; loss-of-function mutation: reduced sodium current activity and repetitive firing in cortical interneurons | Dravet | Schutte et al. 2014 |
| SCN1A KI, K1270T (Drosophila) | K1270T mutation | Thermal seizures; gain-of-function mutation: increased sodium current conductive range than control | GEFS+ | Schutte et al. 2014 |
From Galanopoulou and Moshé 2015; modified, with permission, from Elsevier.
CKO, conditional knockout; GEFS+, genetic epilepsies with febrile seizures plus; KO, knockout; KI, knockin; SCN, sodium channel; PN, postnatal day; GABA, γ-aminobutyric acid; BAC, bacterial artificial chromosome; IPSCs, induced pluripotent stem cells.