title: Status epilepticus in mice deficient for succinate semialdehyde dehydrogenase: GABAA receptor-mediated mechanisms.
abstract: 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 GABA(A) receptor (GABA(A)R) in SSADH-deficient mice. A selective decrease in binding of [(35)S]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 [(35)S]tert-butylbicyclophosphorothionate binding, generalized convulsive seizures emerged that rapidly evolved into status epilepticus. We also observed a substantial downregulation of the beta(2) subunit of GABA(A)R, a reduction in GABA(A)-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 GABA(A)R may be involved in the development of seizures in SSDAH-deficient mice. Elucidation of the precise fundamental mechanisms of the perturbation of the GABA(A)R-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.
authors.affiliation: Brain and Behavior Program, Faculty of Medicine, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Andrea
authors.initials: A
authors.lastname: Buzzi
authors.forename: Marina
authors.initials: M
authors.lastname: Frantseva
authors.forename: Jose Perez L
authors.initials: JP
authors.lastname: Velazquez
authors.forename: Miguel
authors.initials: M
authors.lastname: Cortez
authors.forename: Chunche
authors.initials: C
authors.lastname: Liu
authors.forename: Liqing
authors.initials: L
authors.lastname: Shen
authors.forename: K Michael
authors.initials: KM
authors.lastname: Gibson
authors.forename: O Carter
authors.initials: OC
authors.lastname: Snead
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D003292:Convulsants / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000378:metabolism; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D013226:Status Epilepticus / Q000201:enzymology* / Q000235:genetics; D050644:Succinate-Semialdehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D013462:Sulfur Radioisotopes / Q000378:metabolism
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D009943:Organophosphorus Compounds; D021122:Protein Subunits; D011963:Receptors, GABA-A; D013462:Sulfur Radioisotopes; C107353:CGP 54626; C037476:tert-butylbicyclophosphorothionate; D050644:Succinate-Semialdehyde Dehydrogenase