title: Restoration of norepinephrine-modulated contextual memory in a mouse model of Down syndrome.
abstract: Down syndrome (trisomy 21) is the most common cause of mental retardation in children and leads to marked deficits in contextual learning and memory. In rodents, these tasks require the hippocampus and are mediated by several inputs, particularly those originating in the locus coeruleus. These afferents mainly use norepinephrine as a transmitter. To explore the basis for contextual learning defects in Down syndrome, we examined the Ts65Dn mouse model. These mice, which have three copies of a fragment of mouse chromosome 16, exhibited significant deficits in contextual learning together with dysfunction and degeneration of locus coeruleus neurons. However, the postsynaptic targets of innervation remained responsive to noradrenergic receptor agonists. Indeed, despite advanced locus coeruleus degeneration, we were able to reverse contextual learning failure by using a prodrug for norepinephrine called l-threo-3,4-dihydroxyphenylserine, or xamoterol, a beta(1)-adrenergic receptor partial agonist. Moreover, an increased gene dosage of App, in the context of Down syndrome, was necessary for locus coeruleus degeneration. Our findings raise the possibility that restoring norepinephrine-mediated neurotransmission could reverse cognitive dysfunction in Down syndrome.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford Medical School, Stanford, CA 94305, USA. asalehi@stanford.edu
authors.forename: A
authors.initials: A
authors.lastname: Salehi
authors.forename: M
authors.initials: M
authors.lastname: Faizi
authors.forename: D
authors.initials: D
authors.lastname: Colas
authors.forename: J
authors.initials: J
authors.lastname: Valletta
authors.forename: J
authors.initials: J
authors.lastname: Laguna
authors.forename: R
authors.initials: R
authors.lastname: Takimoto-Kimura
authors.forename: A
authors.initials: A
authors.lastname: Kleschevnikov
authors.forename: S L
authors.initials: SL
authors.lastname: Wagner
authors.forename: P
authors.initials: P
authors.lastname: Aisen
authors.forename: M
authors.initials: M
authors.lastname: Shamloo
authors.forename: W C
authors.initials: WC
authors.lastname: Mobley
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000503:physiopathology* / Q000523:psychology; D007859:Learning Disabilities; D008568:Memory; D051379:Mice; D009638:Norepinephrine / Q000502:physiology*
chemical_list: D009638:Norepinephrine