期刊
EUROPEAN NEUROPSYCHOPHARMACOLOGY
卷 25, 期 6, 页码 889-901出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.euroneuro.2015.03.012
关键词
Intellectual disabilities; NMDA receptors; Transgenic mice; Neural plasticity; Energy metabolism; Behavioral phenotyping
资金
- Jerome Lejeune Foundation (France)
- AIRETT (Italy)
- IRE-IFO [RF2008]
- European Research Projects on Rare Diseases
- IRSF HeART Award [3107]
- Research (MIUR)-Program FIRB-MERIT [1-RBNE08HWLZ-012]
Rho GTPases are molecules critically involved in neuronal plasticity and cognition. We have previously reported that modulation of brain Rho GTPases by the bacterial toxin CNF1 rescues the neurobehavioral phenotype in MeCP2-308 male mice, a model of Rett syndrome (RU). RU is a rare X-linked neurodevelopmental disorder and a genetic cause of intellectual disability, for which no effective therapy is available. Mitochondriat dysfunction has been proposed to be involved in the mechanism of the disease pathogenesis. Here we demonstrate that modulation of Rho GTPases by CNF1 rescues the reduced mitochondrial ATP production via oxidative phosphorylation in the brain of MeCP2-308 heterozygous female mice, the condition which more closely recapitulates that of RU patients. In RU mouse brain, CNF1 also restores the alterations in the activity of the mitochondrial respiratory chain (MRC) complexes and of ATP synthase, the molecular machinery responsible for the majority of cell energy production. Such effects were achieved through the upregulation of the protein content of those MRC complexes subunits, which were defective in RU mouse brain. Restored mitochondrial functionality was accompanied by the rescue of deficits in cognitive function (spatial reference memory in the Barnes maze), synaptic plasticity (long-term potentiation) and Tyr1472 phosphorylation of GluN2B, which was abnormally enhanced in the hippocampus of RU mice. Present findings bring into light previously unknown functional mitochondrial alterations in the brain of female mice modeling RU and provide the first evidence that RU brain mitochondrial dysfunction can be rescued by modulation of Rho GTPases. (C) 2015 Elsevier B.V. and ECNP. All rights reserved.
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