title: Oxidative burden and mitochondrial dysfunction in a mouse model of Rett syndrome.
abstract: Rett syndrome is an X chromosome-linked neurodevelopmental disorder associated with cognitive impairment, motor dysfunction and breathing irregularities causing intermittent hypoxia. Evidence for impaired mitochondrial function is also accumulating. A subunit of complex III is among the potentially dys-regulated genes, the inner mitochondrial membrane is leaking protons, brain ATP levels seem reduced, and Rett patient blood samples confirm increased oxidative damage. We therefore screened for mitochondrial dysfunction and impaired redox balance. In hippocampal slices of a Rett mouse model (Mecp2(-/y)) we detected an increased FAD/NADH baseline-ratio indicating intensified oxidization. Cyanide-induced anoxia caused similar decreases in FAD/NADH ratio and mitochondrial membrane potential in both genotypes, but Mecp2(-/y) mitochondria seemed less polarized. Quantifying cytosolic redox balance with the genetically-encoded optical probe roGFP1 confirmed more oxidized baseline conditions, a more vulnerable redox-balance, and more intense responses of Mecp2(-/y) hippocampus to oxidative challenge and mitochondrial impairment. Trolox treatment improved the redox baseline of Mecp2(-/y) hippocampus and dampened its exaggerated responses to oxidative challenge. Microarray analysis of the hippocampal CA1 subfield did not detect alterations of key mitochondrial enzymes or scavenging systems. Yet, quantitative PCR confirmed a moderate upregulation of superoxide dismutase 1 in Mecp2(-/y) hippocampus, which might be a compensatory response to the increased oxidative burden. Since several receptors and ion-channels are redox-modulated, the mitochondrial and redox changes which already manifest in neonates could contribute to the hyperexcitability and diminished synaptic plasticity in MeCP2 deficiency. Therefore, targeting cellular redox balance might qualify as a potential pharmacotherapeutic approach to improve neuronal network function in Rett syndrome.
authors: DFG Research Center Molecular Physiology of the Brain (CMPB), Zentrum für Physiologie und Pathophysiologie, Abteilung Neuro- und Sinnesphysiologie, Georg-August-Universität Göttingen, Universitätsmedizin, Humboldtallee 23, D-37073 Göttingen, Germany.
authors: Emanuel
authors: E
authors: Grosser
authors: Ursula
authors: U
authors: Hirt
authors: Oliwia A
authors: OA
authors: Janc
authors: Christiane
authors: C
authors: Menzfeld
authors: Marc
authors: M
authors: Fischer
authors: Belinda
authors: B
authors: Kempkes
authors: Steffen
authors: S
authors: Vogelgesang
authors: Till U
authors: TU
authors: Manzke
authors: Lennart
authors: L
authors: Opitz
authors: Gabriela
authors: G
authors: Salinas-Riester
authors: Michael
authors: M
authors: Müller
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D051783:Methyl-CpG-Binding Protein 2; D017382:Reactive Oxygen Species