Table 2.
Comparative description of features of rodent models of IS and associated etiologies
| Mouse model | Genetic defect/induction method | Viability | Spasms | Other seizures | Cognitive/neurodevelopmental deficits | Pathology | References |
|---|---|---|---|---|---|---|---|
| Arx KO | Stop codon, exon 2 | Perinatal death | No data | N/A | N/A (lethal) | 54 | |
| Arx −/Y | Perinatal death | N/A (lethal)(In humans: hypothalamic dysregulation, early death) | Gene‐specific expression changes in ZI and TRN; loss of dopaminergic neurons in ZI; reduced expression of GAD67 in ZI/TRN | 88 | |||
| Arx −/Y Emx1Cre | cKO in pallial progenitor cells of cortical projection neurons | Not reported (vEEG in adulthood) | No (96 h vEEG) | Less anxiety/sociabilityHyperactiveNormal spatial learning/memory/fear memory | No interneuronopathy Reduced cortical thickness, CC/AC hypoplasia, smaller amygdala | 63 | |
| Arx −/Y CKO | Dlx5/6ClG cKO in ganglionic eminence interneuronal progenitors | ≥120 days, but significant perinatal mortality | Spasms in adulthood | Racine stage 5 seizures ≥PN14 | NR | Interneuronopathy P14: reduced ARX+ cells in upper cortical layers and hippocampus; reduced CB+ cells in hippocampus; reduced vNPY+ cells in the neocortex (males only); no change in SST+ neurons; decrease in PRV+ cells in the hippocampus and increase in the neocortex (males only). Adult: reduced CB+ cells in neocortex and hippocampus; reduced CR+ cells in the neocortex; no change in SST+ neurons | 54, 57 |
| Arx 333ins(GCG)7/Y | pA1, 7GCG triplet insertion | Most die ≤3 months | No | 70% have GTC (1 month old); no interictal spikes | Impaired learning, motor coordination, increased locomotor activity and anxiety Yes in humans; hypothalamic dysfunction | Interneuronopathy more severe in striatum (reduced SST, NPY, NOS, and lack of cholinergic interneurons) than cortex; ectopic NPY expression in mossy fibers in mice with seizures | 61 |
| Arx 333ins(GCG)7/Y | pA1, 7GCG triplet insertion | No | PN15–17: No clinical seizures; spontaneous ictal/interictal discharges (CA1, in vitro) | NR | No interneuronopathy in cortex and hippocampus (PN14‐15); glutamate network remodeling | 62 | |
| Arx (GCG)10+7 | pA1, 8GCG triplet insertion | Spasms PN7–11 | Seizures with arrest; limbic, GTC; interictal spikes | Yes Low anxiety, impaired associative learning and social interactions | Interneuronopathy: reduced CB interneurons in the cortex, hippocampus, and striatum; reduced cholinergic and NPY interneurons in striatum; no deficits in PRV or CR interneurons | 58 | |
| Arx PL/Y | P355L | ≥6 months | No | Rare (1/10 mice had tonic seizure) Low threshold to bicuculline seizures | Slightly impaired learning; impaired learning, motor coordination, increased locomotor activity and anxiety | Interneuronopathy more severe in striatum than cortex [less GABAergic (SST, NPY, NOS) and cholinergic neurons in striatum, medial septum, ventral forebrain]; normal size neonatal brains | 61 |
| Arx PR/Y | P355L | Perinatal death (by PN1) | No data | N/A | N/A (lethal) | Interneuronopathy severe at both cerebral cortex and striatum (severe impairment of tangential and radial migration); microcephaly | 61 |
| Apc CKO in CamKII neurons | CKO deletion of Apc gene in excitatory cortical and striatal inhibitory neurons (negative regulator of β‐catenin) | Through adulthood | Flexion‐extension spasms (PN5–14) | Adults: spontaneous electroclinical seizures | Adults: learning, memory deficits, impaired sociability, stereotypies | APC/β‐catenin pathway malformation; interneuronal deficits are not reported in these mice. | 170, 171 |
| Apc CKO in Dlx5/6 or I12b interneurons | CKO deletion of Apc gene in Dlx5/6 (embryonic) or I12b (late postnatal) interneurons | Dlx5/6: Early death (up to PN7) I12b: Improved survival | No data | No data | No data | Impaired tangential migration of interneurons | 172 |
| Apc CKO in Nex projection neurons | CKO deletion of Apc gene in Nex projection neurons | No data | No data | No data | No data | No impairment of the migration of interneuron or projection neurons | 172 |
| Multiple‐hit rat model | R. intracerebral doxorubicin/lipopolysaccharide (PN3), PCPA (PN5) | Through adulthood | Spasms (PN4–13) | Other seizures after PN9; spontaneous motor seizures in adulthood | Impaired motor milestones; impaired spatial learning/memory/sociability | Right cortical/hemispheric/periventricular lesion; interneuronopathy: reduced PRV interneurons contralateral to infusion | 32, 173, 174, 175, 176 |
| Tetrodotoxin (TTX) rat model | TTX chronic infusion in the cortex or hippocampus (PN10–38) | Through adulthood | Spasms ˜PN21 till adulthood | Yes | NR | Effect on interneurons not reported; focal neocortical lesion at site of infusion | 69, 177 |
AC, anterior commissure; Apc, adenomatous polyposis coli; Arx, aristaless related homeobox gene; CA1, cornu ammonis field 1; CamKII, calcium calmodulin protein kinase II; CB, calbindin; CC, corpus callosum; CKO, conditional knockout; CR, calretinin; Dlx, distal‐less homeobox; GTC, generalized tonic‐clonic seizures; KO, knockout; N/A, not applicable; Nex, neuronal helix‐loop‐helix protein; NOS, nitric oxide synthase; NPY, neuropeptide Y; NR, not reported; pA1, 1st polyalanine repeat; PCPA, p‐chlorophenylalanine; PN, postnatal; PRV, parvalbumin; SST, somatostatin; TRN, thalamic reticular nucleus; TTX, tetrodotoxin; vEEG, video‐EEG; ZI, zona incerta.