Table 3.
Selected animal models of DEEs
| Models | Species | Induction Method | Spasms, Age of Onset | Subsequent Epilepsy | Behavioral/Neurodevelopmental Deficits | Response to ACTH/Vigabatrin | Model of: | References |
|---|---|---|---|---|---|---|---|---|
| Models of ES | ||||||||
| Acute | ||||||||
| NMDA | Rat, mouse C57 | NMDA ip, PN7–18 | PN7–18 | NR | Rat: Learning and coordination deficits | High-dose ACTH1-39; vigabatrin | Spasms | (169, 172, 177–181) |
| 3–7 days after NMDA (mouse): Increased anxiety, impaired motor coordination and poor memory retention | ||||||||
| NMDA variants | ||||||||
| Prenatal betamethasone/postnatal NMDA | Rat | Betamethasone ip G15; NMDA ip, PN12–15 | PN12-15 | NR | NR after spasm induction | Low-dose ACTH1-39; Vigabatrin | Spasms, ACTH sensitivity | (170, 182–184) |
| Prenatal stress/postnatal NMDA | Rat | Forced restraint (FR) (G15) or forced swim test (FST) (G1–parturition); NMDA ip, PN15 | PN15 | NR | NR after spasm induction | FST/NMDA: Responds to ACTH1-39 | Spasms, stress | (169, 171) |
| FR/NMDA: Responds to repeated low dose ACTH1-39 | ||||||||
| Prenatal MAM/postnatal NMDA | Rat | MAM (2 doses, G15); NMDA ip, PN12–15 (1 or 3 doses) | PN12–15 | NR | NR after spasm induction | No effect of low-dose ACTH | Spasms, dysplasias | (185) |
| Responds to vigabatrin | ||||||||
| Adrenalectomy/postnatal NMDA | Rat | Adrenalectomy (PN10); NMDA ip (PN11) | PN11 | NR | NR after spasm induction | High-dose ACTH1-39 | Spasms | (172) |
| Tsc1gfap −/+ mouse, postnatal NMDA | Mouse, Tsc1flox/flox-GFAP-Cre knockout C57BL/6 and SV129 | As in Tsc1gfap−/+ | NR after spasm induction | NR | Spasms, induced on a genetic background | (186) | ||
| Down syndrome/GBL | Mouse (Ts65Dn), C57BL/6JEiXC3H/HesnJ | γ-Butyrolactone (GBL) ip | 1 wk to 2 mo | NR | NR after spasm induction | Responds to ACTH1-24 but not to ACTH1-39 | Spasms, induced on a genetic background | (187–189) |
| Responds to vigabatrin | ||||||||
| Chronic | ||||||||
| Tetrodotoxin (TTX) | Rat | Intrahippocampal or intracortical TTX, unilateral (PN10–38) | ≥PN21 | Yes | NR | Sensitive to ACTH, vigabatrin | ISS structural, hypsarrhythmia; drug-sensitive | (87, 190–193) |
| Multiple hit | Rat | PN3: Right intracortical LPS, right intraventricular doxorubicin | PN4–13 | Yes | Sociability deficits, learning/memory deficits, stereotypies | Resistant to ACTH; partial/transient response to vigabatrin | ISS structural, drug resistant | (88, 157–163) |
| PN5: PCPA ip | ||||||||
| Arx cKO | Mouse, CD1 and C57BL/6 | Arx deletion from ganglionic eminence neuronal progenitors | Adulthood | Yes | NR | NR | ISS, genetic | (164) |
| Arx KI [Arx (GCG)10+7] | Mouse, 75% C57BL/6; 25% 129S5/SvEvBrd | Expansion of 1st polyalalanine tract repeat (PA1) of Arx | PN7–11 | Yes | Low anxiety, impaired learning and sociability | NR | ISS, genetic | (152, 165, 194) |
| Arx with PA1 or PA2 expansion | Mouse, C57BL/6N-Hsd | PA1 or PA2 expansion of Arx | ≥PN10 to adulthood (myoclonic seizures) | NR | 1–2 mo: Sociability, neuromuscular strength deficits, anxiety and fear | NR | ISS, genetic | (195) |
| Adenomatous polyposis (Apc) | Mouse | Apc gene knockout from excitatory CamKII neurons | Peak at PN9 | Yes | Reduced social interest, increased repetitive behaviors | NR | ISS, genetic | (196) |
| Tsc1+/− | Mouse, C57BL/6 | Heterozygous Tsc1−/+ | PN12–16; observed for 1 day/pup | NR | NR | NR | ISS, genetic | (197) |
| Aged CDKL5, heterozygous females | Mouse, C57BL/6J | Cdkl5R59X/+ or Cdkl5KO/+ | >PN300 female | No (only spasms seen) | NR in females | NR | ISS, genetic | (198) |
| Sociability deficits in males | ||||||||
| Chronic early-life stress | Rat | Unpredictable and fragmented nurturing behaviors in dams (PN2–9 period) | PN17–35; last for 1 or several days | NR | NR | NR | ISS, unknown | (173) |
| Models of Lennox–Gastaut syndrome, atypical absence seizures | ||||||||
| AY9944 | Rat | AY9944 7.5 mg/kg sc (PN2, 8, 14, PN20) | NR | Slow SWD | Cognitive deficits, hyperactivity, anxiety, spatial learning, olfactory recognition deficits | Responsive to DZP, ETH, CGP35348; Worse with CZP, baclofen, γ-OH-butyrate | Chronic atypical absence seizures | (199–205) |
| MAM-AY9944 | Rat | Prenatal MAM/postnatal AY9944 | NR | Slow SWD | NR | Refractory to ETH, VPA, CGP35348, CBZ | Refractory atypical absence seizures | (206) |
| PValb-Dnm1Ftfl/flox | Mouse, C57BL/6J | Dnm1Ftfl/flox in PV cells | NR | PN19–50: SWD, lethal seizures | Tremor | NR | LGS | (207) |
| GABABR1a | Mouse, C57BL/6 | GABABR1a overexpression in forebrain | NR | Slow SWD | Impairment in learning, spatial memory | Responsive to ETH, CGP35348 | Chronic atypical absence seizures | (208) |
| GABABR1b | Mouse | GABABR1b overexpression in forebrain | NR | Slow SWD | Mild impairment in learning, spatial memory | Responsive to ETH, CGP35348 | Chronic atypical absence seizures | (209) |
| NHE1 | Mouse, SJL/J and C57BL/6J | Na+/H+ exchanger null | NR | Slow SWD (3 Hz) (at 4–5 wk); lethal tonic or tonic-clonic seizures | Ataxia;early mortality | NR | Chronic atypical absence seizures | (210) |
| Multiple hit | Rat | PN3: Right intracortical LPS, right intraventricular doxorubicin PN5: PCPA ip | PN4–13 | Adulthood: slow SWD (5–6 Hz), motor seizures in sleep | Sociability deficits, learning/memory deficits, stereotypies | NR | ISS with LGS features | (157) |
| Models of Dravet syndrome | ||||||||
| Scn1a KO | Mouse | Exon 26 deletion, global constitutive | Convulsive seizures, hyperthermia seizures, mortality | Hyperactivity, stereotypies, sociability, and spatial memory deficits | Tested | Dravet | (64) | |
| Scn1a CKO | Mouse, C57BL/6 and 129Sv | Exon 25 deletion, forebrain GABAergic interneurons | Motor seizures, hyperthermia seizures | NR | Dravet | (211) | ||
| Scn1a CKO | Mouse, B6.SJL-Tg(ACTFLPe)9205Dym/J and C57BL/6 | Conditional deletion of exon 7 | Inhibitory neurons | ≥PN16 seizures, occasional death | Hypoactive, jerks, death | Dravet | (212) | |
| Forebrain excitatory neurons | No | NR | (212) | |||||
| Forebrain excitatory neurons and haploinsufficiency in inhibitory neurons | Improved lethality from seizures | NR | Dravet | (212) | ||||
| PV interneurons | ≥PN14 seizures, death | Ataxia (PN10) | Dravet | (212) | ||||
| Scn1a KI, R1407X | Mouse, 129/SvJ and C57BL/6J | Human R1407X nonsense mutation | ≥1 mo: Seizures | Hyperactivity, stereotypies, sociability and spatial memory deficits | Dravet | (65, 213, 214) | ||
| Scn1a KI, S1231R | Drosophila | S1231R mutation, loss of function | Seizures | NR | Dravet | (215) | ||
| Scn1Lab (didys552) | Zebrafish | Scn1Lab mutation (low expression) | Increased locomotor activity, epileptiform activity, seizures | Impaired exploration, decreased mobility | Tested | Dravet | (216) | |
| Scn1Lab−/− | Zebrafish | Scn1Lab null | Increased locomotor activity and epileptiform activity | NR | Tested | Dravet | (217) | |
| Scn1a-A1783V/WT KI | Mouse, C57BL/6J | Scn1a-A1783V/WT KI | Hyperthermia seizures | NR | Tested | Dravet | (218) | |
| Scn1a R1648H KI (after induction of short seizures) | Mouse | Knock-in R1658H missense mutation, global constitutive | Convulsive seizures, hyperthermia seizures, mortality | Hyperactivity, stereotypies, sociability, and spatial memory deficits | Dravet and GEFS+ | (219) | ||
| Other etiology-specific models of DEE | ||||||||
| Kcnq2 KI | Mouse, C57BL/6J | Kcnq2-Y284C/+, Kcnq2-A306T/+ | NR | NR | Retigabine reduces KA-seizures | KCNQ2 DEE | (220) | |
| Kcnq2-Thr274Met/+ | Mouse, 129Sv, C57BL/6N | Kcnq2-Thr274Met/+ | Yes (>PN20) | Spatial learning and memory deficits | NR | KCNQ2 DEE | (221) | |
| Death by 3rd mo (25%) | ||||||||
| Kcna1−/− | Mouse | Kcna1−/− | Yes | NR | Retigabine reduces spontaneous seizures | KCNA1 epilepsy | (222) | |
| Kcnq1-A340E/A340E | Mouse | Kcnq1-A340E/A340E | Rare spontaneous seizures | NR | Retigabine: adverse cardiac effects | KCNQ1 epilepsy | (222) | |
| Pcdh19 KO and heterozygous females | Mouse, 129S5.C57BL/6 | Pcdh19 KO and heterozygous females | NR; increased susceptibility to 6 Hz and flurothyl seizures | NR | PCDH19 DEE | (223) | ||
| Pcdh19-HET | Mouse, C57BL/6N | Pcdh19-HET | Mossy fiber deficits | NR | Pattern completion and separation deficits | NR | PCDH19 DEE | (224) |
| Pcdh19 KO | Mouse, C57BL/6N | Pcdh19 KO | NR | Increased exploratory behavior, reduced anxiety | NR | PCDH19 DEE | (223) | |
| Cdkl5 CKO | Mouse, CD1 | Cdkl5 CKO in glutamatergic or GABAergic neurons | Defective dendritic arborization and spine maturation | Yes when deleted in glutamatergic neurons. | Autistic symptomatology, motor coordination, memory and breathing abnormalities | Epigallatocathechin-3-gallate (EGCG) corrects synaptic deficits | CDKL5 DEE | (225, 226) |
ACTH, adrenocorticotropic hormone; apc, adenomatous polyposis colon; arx, aristaless X-linked homeobox protein; AY9944, trans-1,4-bis-cyclohexane dihydrochloride, cholesterol biosynthesis inhibitor; CDKL5, cyclin-dependent kinase-like 5; CGP35348, GABAB receptor inhibitor; DEE, developmental and epileptic encephalopathy; ES, epileptic spasms; CKO, conditional knockout; CZP, clonazepam; Dnm1, dynamin 1; DZP, diazepam; EGCG, epigallatocathechin-3-gallate; ETH, ethosuximide; GBL, gamma butyrolactone; FR, forced restraint; FST, forced swim test; G, gestational day; GABABR: GABAB receptor; gfap, glial acidic fibrillary protein; HET, heterozygous; ISS, infantile spasms syndrome; Kcna1, potassium voltage-gated channel subfamily a member 1; KCNQ, potassium voltage-gated channel subfamily Q; KI, knockin; KO, knockout; LGS, Lennox–Gastaut syndrome; LPS, lipopolysaccharide; MAM, methyl-azoxy-methanol acetate; NHE1, Na+/H+ exchanger; NMDA, N-methyl-d-aspartate; NR, not reported; PA, polyalanine; PCPA, p-chlorophenylalanine (inhibits serotonin synthesis); PN, postnatal; PV or Pvalb, parvalbumin; Scn1a, sodium channel 1alpha; SWD, spike and slow-wave discharge; tsc, tuberous sclerosis complex; TTX, tetrodotoxin; VPA, valproic acid.