title: Comprehensive behavioral phenotyping of Ts65Dn mouse model of Down syndrome: activation of β1-adrenergic receptor by xamoterol as a potential cognitive enhancer.
abstract: Down syndrome (DS) is the most prevalent form of mental retardation caused by genetic abnormalities in humans. This has been successfully modeled in mice to generate the Ts65Dn mouse, a genetic model of DS. This transgenic mouse model shares a number of physical and functional abnormalities with people with DS, including changes in the structure and function of neuronal circuits. Significant abnormalities in noradrenergic (NE-ergic) afferents from the locus coeruleus to the hippocampus, as well as deficits in NE-ergic neurotransmission are detected in these animals. In the current study we characterized in detail the behavioral phenotype of Ts65Dn mice, in addition to using pharmacological tools for identification of target receptors mediating the learning and memory deficits observed in this model of DS. We undertook a comprehensive approach to mouse phenotyping using a battery of standard and novel tests encompassing: (i) locomotion (Activity Chamber, PhenoTyper, and CatWalk), (ii) learning and memory (spontaneous alternation, delayed matching-to-place water maze, fear conditioning, and Intellicage), and (iii) social behavior. Ts65Dn mice showed increased locomotor activity in novel and home cage environments. There were significant and reproducible deficits in learning and memory tests including spontaneous alternation, delayed matching-to-place water maze, Intellicage place avoidance and contextual fear conditioning. Although Ts65Dn mice showed no deficit in sociability in the 3-chamber test, a marked impairment in social memory was detected. Xamoterol, a β1-adrenergic receptor (β1-ADR) agonist, effectively restored the memory deficit in contextual fear conditioning, spontaneous alternation and novel object recognition. These behavioral improvements were reversed by betaxolol, a selective β1-ADR antagonist. In conclusion, our results demonstrate that this mouse model of Down syndrome displays cognitive deficits which are mediated by an imbalance in the noradrenergic system. In this experimental model of Down syndrome a selective activation of β1-ADR does restore some of these behavioral deficits. Further mechanistic studies will be needed to investigate the failure of noradrenergic system and the role of β1-ADR in cognitive deficit and pathogenesis of DS in people. Restoring NE neurotransmission or a selective activation of β1)-ADR needs to be further investigated for the development of any potential therapeutic strategy for symptomatic relief of memory deficit in DS. Furthermore, due to the significant involvement of noradrenergic system in the cardiovascular function further safety and translational studies will be needed to ensure the safety and efficacy of this approach.
authors.affiliation: Stanford Behavioral and Functional Neuroscience Laboratory, Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford University School of Medicine, USA.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Faizi
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Bader
authors.forename: Christine
authors.initials: C
authors.lastname: Tun
authors.forename: Angelo
authors.initials: A
authors.lastname: Encarnacion
authors.forename: Alexander
authors.initials: A
authors.lastname: Kleschevnikov
authors.forename: Pavel
authors.initials: P
authors.lastname: Belichenko
authors.forename: Nay
authors.initials: N
authors.lastname: Saw
authors.forename: Matthew
authors.initials: M
authors.lastname: Priestley
authors.forename: Richard W
authors.initials: RW
authors.lastname: Tsien
authors.forename: William C
authors.initials: WC
authors.lastname: Mobley
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Shamloo
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D018697:Nootropic Agents / Q000493:pharmacokinetics; D009638:Norepinephrine / Q000172:deficiency / Q000502:physiology; D010641:Phenotype; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D017307:Xamoterol / Q000494:pharmacology*
chemical_list: D018697:Nootropic Agents; D018342:Receptors, Adrenergic, beta-1; D017307:Xamoterol; D009638:Norepinephrine