title: Metabolic fingerprints of altered brain growth, osmoregulation and neurotransmission in a Rett syndrome model.
abstract: BACKGROUND
  Rett syndrome (RS) is the leading cause of profound mental retardation of genetic origin in girls. Since RS is mostly caused by mutations in the MECP2 gene, transgenic animal models such as the Mecp2-deleted ("Mecp2-null") mouse have been employed to study neurological symptoms and brain function. However, an interdisciplinary approach drawing from chemistry, biology and neuroscience is needed to elucidate the mechanistic links between the genotype and phenotype of this genetic disorder.
  
  
  RESULTS
  We performed, for the first time, a metabolomic study of brain extracts from Mecp2-null mice by using high-resolution magnetic resonance spectroscopy. A large number of individual water-soluble metabolites and phospholipids were quantified without prior selection for specific metabolic pathways. Results were interpreted in terms of Mecp2 gene deletion, brain cell function and brain morphology. This approach provided a "metabolic window" to brain characteristics in Mecp2-null mice (n = 4), revealing (i) the first metabolic evidence of astrocyte involvement in RS (decreased levels of the astrocyte marker, myo-inositol, vs. wild-type mice; p = 0.034); (ii) reduced choline phospholipid turnover in Mecp2-null vs. wild-type mice, implying a diminished potential of cells to grow, paralleled by globally reduced brain size and perturbed osmoregulation; (iii) alterations of the platelet activating factor (PAF) cycle in Mecp2-null mouse brains, where PAF is a bioactive lipid acting on neuronal growth, glutamate exocytosis and other processes; and (iv) changes in glutamine/glutamate ratios (p = 0.034) in Mecp2-null mouse brains potentially indicating altered neurotransmitter recycling.
  
  
  CONCLUSIONS
  This study establishes, for the first time, detailed metabolic fingerprints of perturbed brain growth, osmoregulation and neurotransmission in a mouse model of Rett syndrome. Combined with morphological and neurological findings, these results are crucial elements in providing mechanistic links between genotype and phenotype of Rett syndrome. Ultimately, this information can be used to identify novel molecular targets for pharmacological RS treatment.
authors.affiliation: Centre de Résonance Magnétique Biologique et Médicale, UMR Centre National de la Recherche Scientifique 6612, Université de la Méditerranée, Faculté de Médecine, Marseille, France.
authors.forename: Angèle
authors.initials: A
authors.lastname: Viola
authors.forename: Véronique
authors.initials: V
authors.lastname: Saywell
authors.forename: Laurent
authors.initials: L
authors.lastname: Villard
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Cozzone
authors.forename: Norbert W
authors.initials: NW
authors.lastname: Lutz
mesh_terms: D000818:Animals; D001921:Brain / Q000254:growth & development* / Q000378:metabolism* / Q000503:physiopathology; D001923:Brain Chemistry; D002308:Cardiolipins / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018377:Neurotransmitter Agents / Q000378:metabolism; D010641:Phenotype; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009435:Synaptic Transmission / Q000502:physiology*; D014882:Water-Electrolyte Balance / Q000235:genetics / Q000502:physiology*
chemical_list: D002308:Cardiolipins; D051783:Methyl-CpG-Binding Protein 2; D018377:Neurotransmitter Agents; D010743:Phospholipids