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Expression profiling reveals multiple myelin alterations in murine succinate semialdehyde dehydrogenase deficiency
Author(s) -
Donarum Elizabeth A.,
Stephan Dietrich A.,
Larkin Kay,
Murphy Eric J.,
Gupta Maneesh,
Senephansiri Henry,
Switzer Robert C.,
Pearl Phillip L.,
Snead O. Carter,
Jakobs C.,
Gibson K. Michael
Publication year - 2006
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-006-0247-6
Subject(s) - myelin , proteolipid protein 1 , biology , myelin basic protein , neuroactive steroid , endocrinology , gabaergic , medicine , microbiology and biotechnology , biochemistry , gabaa receptor , central nervous system , receptor , inhibitory postsynaptic potential
Summary 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.