Abstracts

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 g-hydroxybutyric acid (GHB) and g -aminobutyric acid (GABA) in brain, blood, and urine. GHB is known to induce absence-like seizures that have been shown to decrease expression of the glutamate receptor subunit B (GluR2). We tested the hypothesis that the high levels of GHB in the SSDH^-/- mouse cause absence-like seizures. Sequential 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 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 SWD were significantly prolonged by g-hydroxybutyrate. Seizures in SSADH-/- were abolished by, ethosuximide, and the GABABR antagonist CGP 35348 but returned as the drugs were eliminated. Atypical features of Absence seizures in this model are spike[ndash]wave (SWD) from thalamocortical origin, and are associated with vibrissal twitching and frozen immobility. Seizures in SSADH null mice may be a useful tool to further investigate the molecular mechanisms involved in the pathogenesis of absence and generalized tonic clonic seizures associated with SSADH deficiency. (Supported by NINDS NS-40270, Bloorview Childrens Hospital Foundation)