Status epilepticus in mice deficient for succinate semialdehyde dehydrogenase: GABAA receptor-mediated mechanisms

The epilepsy that occurs in SSADH deficiency has a seizure phenotype similar to that occurring in the SSADH−/− mouse. We examined the expression and function of the GABAA receptor (GABAAR) in SSADH‐deficient mice. A selective decrease in binding of [35S]tert‐butylbicyclophosphorothionate was observed in SSADH−/− mice at postnatal day 7 that was progressive until the third postnatal week of life when, at the nadir of the decreased [35S]tert‐butylbicyclophosphorothionate binding, generalized convulsive seizures emerged that rapidly evolved into status epilepticus. We also observed a substantial downregulation of the β2 subunit of GABAAR, a reduction in GABAA‐mediated inhibitory postsynaptic potentials, and augmented postsynaptic population spikes recorded from hippocampal slices. The SSADH−/− mouse model represents a powerful investigative tool for understanding the pathophysiology of the seizures associated with human SSADH deficiency. These data raise the possibility that progressive dysfunction of the GABAAR may be involved in the development of seizures in SSDAH‐deficient mice. Elucidation of the precise fundamental mechanisms of the perturbation of the GABAAR‐mediated function in SSADH−/− mice could lead to the development of novel treatment modalities designed to reduce the neurological morbidity in children with SSADH deficiency. Ann Neurol 2005