title: Expression profiling reveals multiple myelin alterations in murine succinate semialdehyde dehydrogenase deficiency.
abstract: Succinic semialdehyde dehydrogenase (SSADH) deficiency, a rare genetic defect of GABA degradation recently modelled in mice (SSADH(-/-) mice), manifests early absence seizures that evolve into generalized convulsive seizures and lethal status epilepticus in gene-ablated mice. Disrupted GABA homeostasis, in conjunction with the epileptic phenotype and increased gamma-hydroxybutyric acid (GHB), suggested that expression profiling with the U74Av2 Affymetrix system would reveal dysregulation of receptor genes associated with GABAergic and glutamatergic neurotransmission. Unexpectedly, we found significant downregulation for genes associated with myelin biogenesis and compaction, predominantly in hippocampus and cortex. These results were confirmed by: (1) myelin basic protein (MBP) immunohistochemistry; (2) western blotting of myelin-associated glycoprotein (MAG) and MBP; (3) qRT-PCR analyses of myelin-associated oligodendrocytic basic protein (MOBP), MAG, MBP and proteolipid protein (PLP) in hippocampus, cortex and spinal cord; (4) quantitation of ethanolamine and choline plasmalogens, all core myelin components; (5) evaluation of myelin content in brain sections employing toluidine blue staining; and (6) ultrastructural evaluation of myelin sheath thickness via electron microscopy. We speculate that increased GABA/GHB, acting through GABAergic systems, results in decreased levels of the neurosteroids progesterone and allopregnanolone [Gupta et al (2003) Ann Neurol 54(Supplement 6): S81-S90] and phosphorylation of mitogen-activated protein (MAP) kinase, with resulting myelin protein abnormalities primarily in the cortex of SSADH(-/-) mice.
authors.affiliation: Developmental Neurogenetics Research Laboratory, Barrow Neurological Institute, Phoenix, Arizona, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Donarum
authors.forename: Dietrich A
authors.initials: DA
authors.lastname: Stephan
authors.forename: Kay
authors.initials: K
authors.lastname: Larkin
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Murphy
authors.forename: Maneesh
authors.initials: M
authors.lastname: Gupta
authors.forename: Henry
authors.initials: H
authors.lastname: Senephansiri
authors.forename: Robert C
authors.initials: RC
authors.lastname: Switzer
authors.forename: Phillip L
authors.initials: PL
authors.lastname: Pearl
authors.forename: O Carter
authors.initials: OC
authors.lastname: Snead
authors.forename: C
authors.initials: C
authors.lastname: Jakobs
authors.forename: K Michael
authors.initials: KM
authors.lastname: Gibson
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods*; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009186:Myelin Sheath / Q000235:genetics* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D050644:Succinate-Semialdehyde Dehydrogenase / Q000172:deficiency*
chemical_list: D050644:Succinate-Semialdehyde Dehydrogenase