title: Brain acetylcholine and choline concentrations and dynamics in a murine model of the Fragile X syndrome: age, sex and region-specific changes.
abstract: Fragile X syndrome is a learning disability caused by excess of CGG repeats in the 5' untranslated region of the Fragile X gene (FMR1) silencing its transcription and translation. We used a murine model of this condition, Fmr1 knock-out mice (KO) to study acetylcholine (ACh) metabolism and compared it to that of wild-type control mice (WT). Brain endogenous ACh (D0ACh), free choline (D0Ch), their deuterated variants D4ACh and D4Ch and mole ratios (AChMR and ChMR) were measured by gas chromatography-mass spectrometry in the cerebral hemisphere, cerebral cortex, hippocampus and cerebellum, following D4Ch administration. Regression analysis indicated a significant decrease with age (negative slope) of D4ACh, AChMR, D4Ch and ChMR in WT mice. Age dependence was only present for D4ACh and AChMR in KO mice. Analysis of variance with age as covariate indicated a significant greater D4Ch in the cerebral cortex of KO females when compared to WT females. Contrasts between sexes within genotypes indicated lower D0Ch in cortex and cerebellum of female KO mice but not in WT and lower D4Ch in hippocampus of female KO and WT mice. In conclusion, after adjusting for age, D0ACh concentrations and synthesis from deuterium-labeled Ch were similar in KO and control WT mice in all brain regions. In contrast, significant changes in Ch dynamics were found in hippocampus and cerebral cortex of KO mice that might contribute to the pathogenesis of FXS.
authors.affiliation: Greater Los Angeles VA Healthcare System, United States; David Geffen School of Medicine at UCLA, Department of Physiology, United States. Electronic address: oscremin@ucla.edu.
authors.forename: O U
authors.initials: OU
authors.lastname: Scremin
authors.affiliation: Greater Los Angeles VA Healthcare System, United States.
authors.forename: M
authors.initials: M
authors.lastname: Roch
authors.affiliation: Greater Los Angeles VA Healthcare System, United States.
authors.forename: K M
authors.initials: KM
authors.lastname: Norman
authors.affiliation: Greater Los Angeles VA Healthcare System, United States.
authors.forename: S
authors.initials: S
authors.lastname: Djazayeri
authors.affiliation: Greater Los Angeles VA Healthcare System, United States; David Geffen School of Medicine at UCLA, Department of Medicine, United States.
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Liu
mesh_terms: D000109:Acetylcholine / Q000378:metabolism* / Q000493:pharmacokinetics; D000375:Aging / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002794:Choline / Q000378:metabolism* / Q000493:pharmacokinetics; D003903:Deuterium / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D017711:Nonlinear Dynamics; D012727:Sex Characteristics; D013997:Time Factors
chemical_list: D000109:Acetylcholine; D002794:Choline; D003903:Deuterium; D051860:Fragile X Messenger Ribonucleoprotein 1; C497684:Fmr1 protein, mouse
keywords: GCMS; acetylcholine turnover; cholinergic function; fmr1-KO mice; mice