title: Novel strains of mice deficient for the vesicular acetylcholine transporter: insights on transcriptional regulation and control of locomotor behavior.
abstract: Defining the contribution of acetylcholine to specific behaviors has been challenging, mainly because of the difficulty in generating suitable animal models of cholinergic dysfunction. We have recently shown that, by targeting the vesicular acetylcholine transporter (VAChT) gene, it is possible to generate genetically modified mice with cholinergic deficiency. Here we describe novel VAChT mutant lines. VAChT gene is embedded within the first intron of the choline acetyltransferase (ChAT) gene, which provides a unique arrangement and regulation for these two genes. We generated a VAChT allele that is flanked by loxP sequences and carries the resistance cassette placed in a ChAT intronic region (FloxNeo allele). We show that mice with the FloxNeo allele exhibit differential VAChT expression in distinct neuronal populations. These mice show relatively intact VAChT expression in somatomotor cholinergic neurons, but pronounced decrease in other cholinergic neurons in the brain. VAChT mutant mice present preserved neuromuscular function, but altered brain cholinergic function and are hyperactive. Genetic removal of the resistance cassette rescues VAChT expression and the hyperactivity phenotype. These results suggest that release of ACh in the brain is normally required to "turn down" neuronal circuits controlling locomotion.
authors.affiliation: Molecular Brain Research Group, Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: Cristina
authors.initials: C
authors.lastname: Martins-Silva
authors.forename: Xavier
authors.initials: X
authors.lastname: De Jaeger
authors.forename: Monica S
authors.initials: MS
authors.lastname: Guzman
authors.forename: Ricardo D F
authors.initials: RD
authors.lastname: Lima
authors.forename: Magda S
authors.initials: MS
authors.lastname: Santos
authors.forename: Christopher
authors.initials: C
authors.lastname: Kushmerick
authors.forename: Marcus V
authors.initials: MV
authors.lastname: Gomez
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
authors.forename: Marco A M
authors.initials: MA
authors.lastname: Prado
authors.forename: Vania F
authors.initials: VF
authors.lastname: Prado
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000150:complications / Q000503:physiopathology; D001522:Behavior, Animal / Q000502:physiology*; D005786:Gene Expression Regulation; D056426:Genetic Loci / Q000235:genetics; D006185:Habituation, Psychophysiologic / Q000502:physiology; D006948:Hyperkinesis / Q000150:complications / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000235:genetics*; D016254:Mutagenesis, Insertional / Q000235:genetics; D009469:Neuromuscular Junction / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D050494:Vesicular Acetylcholine Transport Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; C493460:Slc18a3 protein, mouse; D050494:Vesicular Acetylcholine Transport Proteins; D000109:Acetylcholine