caa a22 4500 467932611 CHVBK 20180406152947.0 cr unu---uuuuu 170328e20060201xx s 000 0 eng 10.1007/s10545-006-0247-6 doi (NATIONALLICENCE)springer-10.1007/s10545-006-0247-6 Expression profiling reveals multiple myelin alterations in murine succinate semialdehyde dehydrogenase deficiency [Elektronische Daten] [Elizabeth Donarum, Dietrich Stephan, Kay Larkin, Eric Murphy, Maneesh Gupta, Henry Senephansiri, Robert Switzer, Phillip Pearl, O. Snead, C. Jakobs, K. Gibson] 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. SSIEM and Springer, 2006 Donarum Elizabeth Developmental Neurogenetics Research Laboratory, Barrow Neurological Institute, Phoenix, Arizona, USA aut Stephan Dietrich Neurogenomics Program, Translational Genomics Research Institute, Phoenix, Arizona, USA aut Larkin Kay Departments of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon, USA aut Murphy Eric Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine, Grand Forks, North Dakota, USA aut Gupta Maneesh Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA aut Senephansiri Henry Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA aut Switzer Robert Neuroscience Associates, Knoxville, Tennessee, USA aut Pearl Phillip Departments of Pediatrics and Neurology, Children's National Medical Center, The George Washington University School of Medicine, Washington, D.C., USA aut Snead O. Department of Pediatrics, Division of Neurology and The Program in Brain and Behavior, Faculty of Medicine, Hospital for Sick Children, Toronto, Ontario, Canada aut Jakobs C. Department of Clinical Chemistry, VU Medical Center, Amsterdam, The Netherlands aut Gibson K. Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA aut Journal of Inherited Metabolic Disease Kluwer Academic Publishers 29/1(2006-02-01), 143-156 0141-8955 29:1<143 2006 29 10545 https://doi.org/10.1007/s10545-006-0247-6 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10545-006-0247-6 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Donarum Elizabeth Developmental Neurogenetics Research Laboratory, Barrow Neurological Institute, Phoenix, Arizona, USA aut NATIONALLICENCE 700 1- Stephan Dietrich Neurogenomics Program, Translational Genomics Research Institute, Phoenix, Arizona, USA aut NATIONALLICENCE 700 1- Larkin Kay Departments of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon, USA aut NATIONALLICENCE 700 1- Murphy Eric Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine, Grand Forks, North Dakota, USA aut NATIONALLICENCE 700 1- Gupta Maneesh Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA aut NATIONALLICENCE 700 1- Senephansiri Henry Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA aut NATIONALLICENCE 700 1- Switzer Robert Neuroscience Associates, Knoxville, Tennessee, USA aut NATIONALLICENCE 700 1- Pearl Phillip Departments of Pediatrics and Neurology, Children's National Medical Center, The George Washington University School of Medicine, Washington, D.C., USA aut NATIONALLICENCE 700 1- Snead O. Department of Pediatrics, Division of Neurology and The Program in Brain and Behavior, Faculty of Medicine, Hospital for Sick Children, Toronto, Ontario, Canada aut NATIONALLICENCE 700 1- Jakobs C. Department of Clinical Chemistry, VU Medical Center, Amsterdam, The Netherlands aut NATIONALLICENCE 700 1- Gibson K. Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA aut NATIONALLICENCE 773 0- Journal of Inherited Metabolic Disease Kluwer Academic Publishers 29/1(2006-02-01), 143-156 0141-8955 29:1<143 2006 29 10545 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer