Formoterol, a Long-Acting β2 Adrenergic Agonist, Improves Cognitive Function and Promotes Dendritic Complexity in a Mouse Model of Down Syndrome


      Down syndrome is associated with significant failure in cognitive function. Our previous investigation revealed age-dependent degeneration of locus coeruleus, a major player in contextual learning, in the Ts65Dn mouse model of Down syndrome. We studied whether drugs already available for use in humans can be used to improve cognitive function in these mice.


      We studied the status of β adrenergic signaling in the dentate gyrus of the Ts65Dn mouse model of Down syndrome. Furthermore, we used fear conditioning to study learning and memory in these mice. Postmortem analyses included the analysis of synaptic density, dendritic arborization, and neurogenesis.


      We found significant atrophy of dentate gyrus and failure of β adrenergic signaling in the hippocampus of Ts65Dn mice. Our behavioral analyses revealed that formoterol, a long-acting β2 adrenergic receptor agonist, caused significant improvement in the cognitive function in Ts65Dn mice. Postmortem analyses revealed that the use of formoterol was associated with a significant improvement in the synaptic density and increased complexity of newly born dentate granule neurons in the hippocampus of Ts65Dn mice.


      Our data suggest that targeting β2 adrenergic receptors is an effective strategy for restoring synaptic plasticity and cognitive function in these mice. Considering its widespread use in humans and positive effects on cognition in Ts65Dn mice, formoterol or similar β2 adrenergic receptor agonists with ability to cross the blood brain barrier might be attractive candidates for clinical trials to improve cognitive function in individuals with Down syndrome.

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        • Hassold T.
        • Hunt P.
        To err (meiotically) is human: The genesis of human aneuploidy.
        Nat Rev Genet. 2001; 2: 280-291
        • Parker S.E.
        • Mai C.T.
        • Canfield M.A.
        • Rickard R.
        • Wang Y.
        • Meyer R.E.
        • et al.
        Updated National Birth Prevalence estimates for selected birth defects in the United States, 2004–2006.
        Birth Defects Res A Clin Mol Teratol. 2010; 88: 1008-1016
        • Stancliffe R.J.
        • Lakin K.C.
        • Larson S.A.
        • Engler J.
        • Taub S.
        • Fortune J.
        • et al.
        Demographic characteristics, health conditions, and residential service use in adults with Down syndrome in 25 U.S. states.
        Intellect Dev Disabil. 2012; 50: 92-108
        • Wisniewski K.E.
        • Wisniewski H.M.
        • Wen G.Y.
        Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome.
        Ann Neurol. 1985; 17: 278-282
        • Alford K.A.
        • Slender A.
        • Vanes L.
        • Li Z.
        • Fisher E.M.
        • Nizetic D.
        • et al.
        Perturbed hematopoiesis in the Tc1 mouse model of Down syndrome.
        Blood. 2010; 115: 2928-2937
        • Belichenko P.V.
        • Kleschevnikov A.M.
        • Masliah E.
        • Wu C.
        • Takimoto-Kimura R.
        • Salehi A.
        • et al.
        Excitatory-inhibitory relationship in the fascia dentata in the Ts65Dn mouse model of Down syndrome.
        J Comp Neurol. 2009; 512: 453-466
        • Kleschevnikov A.M.
        • Belichenko P.V.
        • Villar A.J.
        • Epstein C.J.
        • Malenka R.C.
        • Mobley W.C.
        Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome.
        J Neurosci. 2004; 24: 8153-8160
        • Mitra A.
        • Blank M.
        • Madison D.V.
        Developmentally altered inhibition in Ts65Dn, a mouse model of Down syndrome.
        Brain Res. 2012; 1440: 1-8
        • Salehi A.
        • Pohlman B.
        • Mobley W.C.
        Down Syndrome/Trisomy 21.
        in: Squire L.R. The New Encyclopedia of Neuroscience. Elsevier, San Diego2008
        • Duchon A.
        • Raveau M.
        • Chevalier C.
        • Nalesso V.
        • Sharp A.J.
        • Herault Y.
        Identification of the translocation breakpoints in the Ts65Dn and Ts1Cje mouse lines: Relevance for modeling Down syndrome.
        Mamm Genome. 2011; 22: 674-684
        • Sara S.J.
        The locus coeruleus and noradrenergic modulation of cognition.
        Nat Rev Neurosci. 2009; 10: 211-223
        • Millan Sanchez M.
        • Heyn S.N.
        • Das D.
        • Moghadam S.
        • Martin K.J.
        • Salehi A.
        Neurobiological elements of cognitive dysfunction in Down syndrome: Exploring the role of APP.
        Biol Psychiatry. 2012; 71: 403-409
        • Mann D.M.
        • Yates P.O.
        • Marcyniuk B.
        • Ravindra C.R.
        Pathological evidence for neurotransmitter deficits in Down’s syndrome of middle age.
        J Ment Defic Res. 1985; 29: 125-135
        • Salehi A.
        • Faizi M.
        • Colas D.
        • Valletta J.
        • Laguna J.
        • Takimoto-Kimura R.
        • et al.
        Restoration of norepinephrine-modulated contextual memory in a mouse model of Down syndrome.
        Sci Transl Med. 2009; 1 (7ra17)
        • Lockrow J.
        • Boger H.
        • Gerhardt G.
        • Aston-Jones G.
        • Bachman D.
        • Granholm A.C.
        A noradrenergic lesion exacerbates neurodegeneration in a Down syndrome mouse model.
        J Alzheimers Dis. 2011; 23: 471-489
        • Kaufmann H.
        • Mathias C.
        • Low P.
        • Biaggioni I.
        • Freeman R.
        Experience with droxidopa (NortheraTM) in a phase III multinational, placebo-controlled, parallel group, induction-design study to assess clinical benefit and safety in subjects with neurogenic orthostatic hypotension.
        Clin Auton Res. 2010; 20: 289-330
        • Aimone J.B.
        • Wiles J.
        • Gage F.H.
        Computational influence of adult neurogenesis on memory encoding.
        Neuron. 2009; 61: 187-202
        • Nicholas A.P.
        • Pieribone V.A.
        • Hokfelt T.
        Cellular localization of messenger RNA for beta-1 and beta-2 adrenergic receptors in rat brain: An in situ hybridization study.
        Neuroscience. 1993; 56: 1023-1039
        • Gibbs M.E.
        • Summers R.J.
        Contrasting roles for beta1, beta2 and beta3-adrenoceptors in memory formation in the chick.
        Neuroscience. 2005; 131: 31-42
        • Li S.
        • Jin M.
        • Zhang D.
        • Yang T.
        • Koeglsperger T.
        • Fu H.
        • et al.
        Environmental novelty activates β2-adrenergic signaling to prevent the impairment of hippocampal LTP by Aβ Oligomers.
        Neuron. 2013; 77: 929-941
        • Yang Q.
        • Rasmussen S.A.
        • Friedman J.M.
        Mortality associated with Down’s syndrome in the USA from 1983 to 1997: A population-based study.
        Lancet. 2002; 359: 1019-1025
        • Baker J.G.
        The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors.
        Br J Pharmacol. 2010; 160: 1048-1061
        • LaForce C.
        • Prenner B.M.
        • Andriano K.
        • Lavecchia C.
        • Yegen U.
        Efficacy and safety of formoterol delivered via a new multidose dry powder inhaler (Certihaler) in adolescents and adults with persistent asthma.
        J Asthma. 2005; 42: 101-106
        • Sasaki H.
        • Kamimura H.
        • Shiobara Y.
        • Esumi Y.
        • Takaichi M.
        • Yokoshima T.
        Disposition and metabolism of formoterol fumarate, a new bronchodilator, in rats and dogs.
        Xenobiotica. 1982; 12: 803-812
        • McNamee E.N.
        • Ryan K.M.
        • Griffin E.W.
        • Gonzalez-Reyes R.E.
        • Ryan K.J.
        • Harkin A.
        • et al.
        Noradrenaline acting at central beta-adrenoceptors induces interleukin-10 and suppressor of cytokine signaling-3 expression in rat brain: Implications for neurodegeneration.
        Brain Behav Immun. 2010; 24: 660-671
        • Lecaillon J.B.
        • Kaiser G.
        • Palmisano M.
        • Morgan J.
        • Della Cioppa G.
        Pharmacokinetics and tolerability of formoterol in healthy volunteers after a single high dose of Foradil dry powder inhalation via Aerolizer.
        Eur J Clin Pharmacol. 1999; 55: 131-138
        • Faizi M.
        • Bader P.L.
        • Tun C.
        • Encarnacion A.
        • Kleschevnikov A.
        • Belichenko P.
        • et al.
        Comprehensive behavioral phenotyping of Ts65Dn mouse model of Down Syndrome: Activation of β1-adrenergic receptor by xamoterol as a potential cognitive enhancer.
        Neurobiol Dis. 2011; 43: 397-413
        • Escorihuela R.M.
        • Fernandez-Teruel A.
        • Vallina I.F.
        • Baamonde C.
        • Lumbreras M.A.
        • Dierssen M.
        • et al.
        A behavioral assessment of Ts65Dn mice: A putative Down syndrome model.
        Neurosci Lett. 1995; 199: 143-146
        • Ruby N.F.
        • Fernandez F.
        • Zhang P.
        • Klima J.
        • Heller H.C.
        • Garner C.C.
        Circadian locomotor rhythms are normal in Ts65Dn “Down syndrome” mice and unaffected by pentylenetetrazole.
        J Biol Rhythms. 2010; 25: 63-66
        • Incerti M.
        • Toso L.
        • Vink J.
        • Roberson R.
        • Nold C.
        • Abebe D.
        • et al.
        Prevention of learning deficit in a Down syndrome model.
        Obstet Gynecol. 2011; 117: 354-361
        • Coussons-Read M.E.
        • Crnic L.S.
        Behavioral assessment of the Ts65Dn mouse, a model for Down syndrome: Altered behavior in the elevated plus maze and open field.
        Behav Genet. 1996; 26: 7-13
        • Heneka M.T.
        • Nadrigny F.
        • Regen T.
        • Martinez-Hernandez A.
        • Dumitrescu-Ozimek L.
        • Terwel D.
        • et al.
        Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine.
        Proc Natl Acad Sci U S A. 2010; 107: 6058-6063
        • Kimelberg H.K.
        Receptors on astrocytes—what possible functions?.
        Neurochem Int. 1995; 26: 27-40
        • Tanaka K.F.
        • Kashima H.
        • Suzuki H.
        • Ono K.
        • Sawada M.
        Existence of functional beta1- and beta2-adrenergic receptors on microglia.
        J Neurosci Res. 2002; 70: 232-237
        • Pascual R.
        • Zamora-Leon S.P.
        • Valero-Cabre A.
        Effects of postweaning social isolation and re-socialization on the expression of vasoactive intestinal peptide (VIP) and dendritic development in the medial prefrontal cortex of the rat.
        Acta Neurobiol Exp (Wars). 2006; 66: 7-14
        • Kiyota T.
        • Ingraham K.L.
        • Jacobsen M.T.
        • Xiong H.
        • Ikezu T.
        FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer’s disease and has therapeutic implications for neurocognitive disorders.
        Proc Natl Acad Sci U S A. 2011; 108: E1339-E1348
        • Bondareff W.
        • Mountjoy C.Q.
        • Roth M.
        Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia.
        Neurology. 1982; 32: 164-168
        • Braak H.
        • Thal D.R.
        • Ghebremedhin E.
        • Del Tredici K.
        Stages of the pathologic process in Alzheimer disease: Age categories from 1 to 100 years.
        J Neuropathol Exp Neurol. 2011; 70: 960-969
        • Milner T.A.
        • Shah P.
        • Pierce J.P.
        beta-adrenergic receptors primarily are located on the dendrites of granule cells and interneurons but also are found on astrocytes and a few presynaptic profiles in the rat dentate gyrus.
        Synapse. 2000; 36: 178-193
        • Dierssen M.
        • Vallina I.F.
        • Baamonde C.
        • Garcia-Calatayud S.
        • Lumbreras M.A.
        • Florez J.
        Alterations of central noradrenergic transmission in Ts65Dn mouse, a model for Down syndrome.
        Brain Res. 1997; 749: 238-244
        • Baamonde C.
        • Martinez-Cue C.
        • Florez J.
        • Dierssen M.
        G-protein-associated signal transduction processes are restored after postweaning environmental enrichment in Ts65Dn, a Down syndrome mouse model.
        Dev Neurosci. 2011; 33: 442-450
        • Vis J.C.
        • Duffels M.G.
        • Winter M.M.
        • Weijerman M.E.
        • Cobben J.M.
        • Huisman S.A.
        • et al.
        Down syndrome: A cardiovascular perspective.
        J Intellect Disabil Res. 2009; 53: 419-425
        • Sekerel B.E.
        • Sahiner U.M.
        • Can M.
        • Abali G.
        • Alehan D.
        • Aytemir K.
        The effects of inhaled formoterol on the autonomic nervous system in adolescents with asthma.
        Ann Allergy Asthma Immunol. 2011; 107: 266-272
        • McNamee E.N.
        • Griffin E.W.
        • Ryan K.M.
        • Ryan K.J.
        • Heffernan S.
        • Harkin A.
        • et al.
        Noradrenaline acting at beta-adrenoceptors induces expression of IL-1beta and its negative regulators IL-1ra and IL-1RII, and drives an overall anti-inflammatory phenotype in rat cortex.
        Neuropharmacology. 2010; 59: 37-48
        • Mayfield K.P.
        • Soszynski D.
        • Kozak W.
        • Kozak A.
        • Rudolph K.
        • Kluger M.J.
        Beta-adrenergic receptor subtype effects on stress fever and thermoregulation.
        Neuroimmunomodulation. 1999; 6: 305-317
        • Murchison C.F.
        • Zhang X.Y.
        • Zhang W.P.
        • Ouyang M.
        • Lee A.
        • Thomas S.A.
        A distinct role for norepinephrine in memory retrieval.
        Cell. 2004; 117: 131-143
        • Busquets S.
        • Figueras M.T.
        • Fuster G.
        • Almendro V.
        • Moore-Carrasco R.
        • Ametller E.
        • et al.
        Anticachectic effects of formoterol: A drug for potential treatment of muscle wasting.
        Cancer Res. 2004; 64: 6725-6731
        • Bartow R.A.
        • Brogden R.N.
        Formoterol. An update of its pharmacological properties and therapeutic efficacy in the management of asthma.
        Drugs. 1998; 55: 303-322
        • Bensch G.
        • Lapidus R.J.
        • Levine B.E.
        • Lumry W.
        • Yegen U.
        • Kiselev P.
        • et al.
        A randomized, 12-week, double-blind, placebo-controlled study comparing formoterol dry powder inhaler with albuterol metered-dose inhaler.
        Ann Allergy Asthma Immunol. 2001; 86: 19-27
        • Pollonini G.
        • Gao V.
        • Rabe A.
        • Palminiello S.
        • Albertini G.
        • Alberini C.M.
        Abnormal expression of synaptic proteins and neurotrophin-3 in the Down syndrome mouse model Ts65Dn.
        Neuroscience. 2008; 156: 99-106
        • Raineki C.
        • Holman P.J.
        • Debiec J.
        • Bugg M.
        • Beasley A.
        • Sullivan R.M.
        Functional emergence of the hippocampus in context fear learning in infant rats.
        Hippocampus. 2010; 20: 1037-1046
        • Kaczmarek L.
        Expression of c-fos and other genes encoding transcription factors in long-term potentiation.
        Behav Neural Biol. 1992; 57: 263-266
        • Contestabile A.
        • Fila T.
        • Ceccarelli C.
        • Bonasoni P.
        • Bonapace L.
        • Santini D.
        • et al.
        Cell cycle alteration and decreased cell proliferation in the hippocampal dentate gyrus and in the neocortical germinal matrix of fetuses with Down syndrome and in Ts65Dn mice.
        Hippocampus. 2007; 17: 665-678
        • Contestabile A.
        • Fila T.
        • Cappellini A.
        • Bartesaghi R.
        • Ciani E.
        Widespread impairment of cell proliferation in the neonate Ts65Dn mouse, a model for Down syndrome.
        Cell Prolif. 2009; 42: 171-181
        • Chakrabarti L.
        • Scafidi J.
        • Gallo V.
        • Haydar T.F.
        Environmental enrichment rescues postnatal neurogenesis defect in the male and female Ts65Dn mouse model of Down syndrome.
        Dev Neurosci. 2011; 33: 428-441
        • Clark S.
        • Schwalbe J.
        • Stasko M.R.
        • Yarowsky P.J.
        • Costa A.C.
        Fluoxetine rescues deficient neurogenesis in hippocampus of the Ts65Dn mouse model for Down syndrome.
        Exp Neurol. 2006; 200: 256-261
        • Contestabile A.
        • Fila T.
        • Bartesaghi R.
        • Ciani E.
        Choline acetyltransferase activity at different ages in brain of Ts65Dn mice, an animal model for Down’s syndrome and related neurodegenerative diseases.
        J Neurochem. 2006; 97: 515-526
        • Goodison K.L.
        • Parhad I.M.
        • White 3rd, C.L.
        • Sima A.A.
        • Clark A.W.
        Neuronal and glial gene expression in neocortex of Down’s syndrome and Alzheimer’s disease.
        J Neuropathol Exp Neurol. 1993; 52: 192-198
        • Zdaniuk G.
        • Wierzba-Bobrowicz T.
        • Szpak G.M.
        • Stepien T.
        Astroglia disturbances during development of the central nervous system in fetuses with Down’s syndrome.
        Folia Neuropathol. 2011; 49: 109-114
        • Mallei A.
        • Shi B.
        • Mocchetti I.
        Antidepressant treatments induce the expression of basic fibroblast growth factor in cortical and hippocampal neurons.
        Mol Pharmacol. 2002; 61: 1017-1024
        • Follesa P.
        • Mocchetti I.
        Regulation of basic fibroblast growth factor and nerve growth factor mRNA by beta-adrenergic receptor activation and adrenal steroids in rat central nervous system.
        Mol Pharmacol. 1993; 43: 132-138
        • Edgin J.O.
        • Mason G.M.
        • Allman M.J.
        • Capone G.T.
        • Deleon I.
        • Maslen C.
        • et al.
        Development and validation of the Arizona Cognitive Test Battery for Down syndrome.
        J Neurodev Disord. 2010; 2: 149-164