Absence seizures in succinic semialdehyde dehydrogenase deficient mice: a model of juvenile absence epilepsy.
The succinic semialdehyde dehydrogenase (SSADH) null mouse represents a viable animal model for human SSADH deficiency and is characterized by markedly elevated levels of both gamma-hydroxybutyric acid (GHB) and gamma-aminobutyric acid (GABA) in brain, blood, and urine. GHB is known to induce absence-like seizures and absence seizures have been reported to occur in children with SSADH deficiency. We tested the hypothesis that the phenotype of the SSADH(-/-) mouse shows absence-like seizures because of the inordinately high levels of GHB in the brain of this mutant animal. Sequential electrocorticographic (ECoG) and prolonged video ECoG recordings from chronically implanted electrodes were done on SSADH(-/-), SSADH(+/-), and SSADH(+/+) mice from postnatal day (P) 10 to (P) 21. Spontaneous, recurrent absence-like seizures appeared in the SSADH(-/-) during the second week of life and evolved into generalized convulsive seizures late in the third week of life that were associated with an explosive onset of status epilepticus which was lethal. The seizures in SSADH null mice were consistent with typical absence seizures in rodent with 7 Hz spike-and-wave discharge (SWD) recorded from thalamocortical circuitry, the onset/offset of which was time-locked with ictal behavior characterized by facial myoclonus, vibrissal twitching and frozen immobility. The absence seizures became progressively more severe from P14 to 18 at which time they evolved into myoclonic and generalized convulsive seizures that progressed into a lethal status epilepticus. The absence seizures in SSADH(-/-) were abolished by ethosuximide (ETX) and the GABA(B)R antagonist CGP 35348. The seizure phenotype in the SSADH(-/-) recapitulates that observed in human SSADH deficiency. Hence, SSADH(-/-) may be used to investigate the molecular mechanisms that underpin the pathogenesis of absence and generalized tonic-clonic seizures associated with SSADH deficiency. As well, the SSADH(-/-) may represent a unique animal model of the transition from absence to myoclonic and generalized convulsive seizures that is observed in up to 80% of patients with juvenile absence epilepsy.
Cortez
M A
MA
Division of Neurology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.
Wu
Y
Y
Gibson
K M
KM
Snead
O C
OC
D000445:Aldehyde Oxidoreductases / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004832:Epilepsy, Absence / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D018756:GABA Antagonists / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050644:Succinate-Semialdehyde Dehydrogenase
D018756:GABA Antagonists; D000445:Aldehyde Oxidoreductases; D050644:Succinate-Semialdehyde Dehydrogenase