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.