title: Modulation of Rho GTPases rescues brain mitochondrial dysfunction, cognitive deficits and aberrant synaptic plasticity in female mice modeling Rett syndrome.
abstract: 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 (RTT). RTT is a rare X-linked neurodevelopmental disorder and a genetic cause of intellectual disability, for which no effective therapy is available. Mitochondrial 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 RTT patients. In RTT 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 RTT 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 RTT mice. Present findings bring into light previously unknown functional mitochondrial alterations in the brain of female mice modeling RTT and provide the first evidence that RTT brain mitochondrial dysfunction can be rescued by modulation of Rho GTPases.
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Roma, Italy. Electronic address: bianca.defilippis@iss.it.
authors.forename: Bianca
authors.initials: B
authors.lastname: De Filippis
authors.affiliation: Institute of Biomembranes and Bioenergetics, National Council of Research, Bari, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Valenti
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Roma, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Chiodi
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Roma, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Ferrante
authors.affiliation: Institute of Biomembranes and Bioenergetics, National Council of Research, Bari, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: de Bari
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Roma, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Fiorentini
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Roma, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Domenici
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Roma, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Ricceri
authors.affiliation: Institute of Biomembranes and Bioenergetics, National Council of Research, Bari, Italy.
authors.forename: Rosa Anna
authors.initials: RA
authors.lastname: Vacca
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Roma, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Fabbri
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Roma, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Laviola
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D004195:Disease Models, Animal; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000627:therapeutic use; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D007276:Injections, Intraventricular; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics*; D017470:Receptors, Glutamate / Q000378:metabolism; D015518:Rett Syndrome / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D014792:Visual Acuity / Q000187:drug effects / Q000235:genetics; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D001427:Bacterial Toxins; D045222:Electron Transport Chain Complex Proteins; D029968:Escherichia coli Proteins; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D017470:Receptors, Glutamate; C060296:cytotoxic necrotizing factor type 1; D020741:rho GTP-Binding Proteins
keywords: Behavioral phenotyping; Energy metabolism; Intellectual disabilities; NMDA receptors; Neural plasticity; Transgenic mice