Table 3.
Animal models of Dravet syndrome or GEFS+
| Animal models | Genetic defect | Pathology in interneurons/GABA | Epilepsy | Cognitive/behavioral/other neurological deficits | Human syndrome | References |
|---|---|---|---|---|---|---|
| Scn1a CKO |
Exon 25 deletion, in forebrain GABAergic neurons |
Selective loss of Nav1.1 in forebrain cortical and hippocampal GABAergic neurons |
Spontaneous seizures (stage 3–5, Racine) Premature death after seizures (PN18–22) Thermal‐induced seizures (PN22) |
NR | Dravet | 178 |
| 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 | Dravet | 179 |
| 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 PRV interneurons |
Homozygotes: Spontaneous seizures (PN14); death by PN30 Heterozygotes: Spontaneous seizures, and death after PN16 |
Ataxia (PN10) | ||||
| Scn1a KI, R1407X | Human R1407X nonsense mutation |
Heterozygous:
Reduced number of Nav1.1 expressing GABAergic interneurons in cerebral cortex and hippocampus Intact number of GABAergic interneurons |
Heterozygous:
Low threshold in PTZ seizures Heterozygous and homozygous: Spontaneous seizures (1 month old) |
Heterozygous:
Hyperactivity, stereotypies, social interaction deficits, impaired context‐dependent spatial memory, aversion to novel odors Deficits in sociability and fear memory rescued by low‐dose clonazepam |
Dravet | 79, 130, 180 |
| Scn1a KI, R1648H | Human R1648H mutation | Cortical interneurons with reduced firing, slower recovery from inactivation and increased use‐dependent inactivation of sodium channels |
Homozygous: Spontaneous generalized seizures (jump, jerks, head nodding, clonus, hindlimb extension) Lower thresholds to hyperthermic or flurothyl seizures Premature death PN16‐26 Heterozygous: less severe phenotype than homozygous |
NR | GEFS+ | 181 |
| BAC transgene with R1648H mutation | R1648H mutation | Cortical interneurons with slower recovery from inactivation and increased use‐dependent inactivation of sodium channels | More severe kainic acid seizures | NR | GEFS+ | 182, 183 |
| Scn1a KI, S1231R (Drosophila) | S1231R mutation | Loss of function mutation: Reduced sodium current activity and repetitive firing in cortical interneurons | Spontaneous and thermal seizures | NR | Dravet | 80 |
BAC, bacterial artificial chromosome; CKO, conditional knockout; GABA, γ‐aminobutyric acid; GEFS+, generalized epilepsy with febrile seizures plus; KI, knockin; KO, knockout; NR, not reported; PN, postnatal; SCN1A, sodium channel, voltage‐gated, type I, alpha subunit.
Modified from Galanopoulou and Moshé (2015)184 with permission from Elsevier.