title: Formoterol, a long-acting β2 adrenergic agonist, improves cognitive function and promotes dendritic complexity in a mouse model of Down syndrome.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences (VD, JWA, AS); Veterans Administration Palo Alto Health Care System (VD, BM, DD, SM, KJM, BL, PN, DP, JWA, AS), Palo Alto, California.
authors.forename: Van
authors.initials: V
authors.lastname: Dang
authors.affiliation: Veterans Administration Palo Alto Health Care System (VD, BM, DD, SM, KJM, BL, PN, DP, JWA, AS), Palo Alto, California.
authors.forename: Brian
authors.initials: B
authors.lastname: Medina
authors.affiliation: Veterans Administration Palo Alto Health Care System (VD, BM, DD, SM, KJM, BL, PN, DP, JWA, AS), Palo Alto, California.
authors.forename: Devsmita
authors.initials: D
authors.lastname: Das
authors.affiliation: Veterans Administration Palo Alto Health Care System (VD, BM, DD, SM, KJM, BL, PN, DP, JWA, AS), Palo Alto, California.
authors.forename: Sarah
authors.initials: S
authors.lastname: Moghadam
authors.affiliation: Veterans Administration Palo Alto Health Care System (VD, BM, DD, SM, KJM, BL, PN, DP, JWA, AS), Palo Alto, California.
authors.forename: Kara J
authors.initials: KJ
authors.lastname: Martin
authors.affiliation: Veterans Administration Palo Alto Health Care System (VD, BM, DD, SM, KJM, BL, PN, DP, JWA, AS), Palo Alto, California.
authors.forename: Bill
authors.initials: B
authors.lastname: Lin
authors.affiliation: Veterans Administration Palo Alto Health Care System (VD, BM, DD, SM, KJM, BL, PN, DP, JWA, AS), Palo Alto, California.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Naik
authors.affiliation: Veterans Administration Palo Alto Health Care System (VD, BM, DD, SM, KJM, BL, PN, DP, JWA, AS), Palo Alto, California.
authors.forename: Devan
authors.initials: D
authors.lastname: Patel
authors.affiliation: Department of Molecular and Cellular Physiology (RN), Stanford University School of Medicine, Stanford.
authors.forename: Rachel
authors.initials: R
authors.lastname: Nosheny
authors.affiliation: Department of Psychiatry and Behavioral Sciences (VD, JWA, AS); Veterans Administration Palo Alto Health Care System (VD, BM, DD, SM, KJM, BL, PN, DP, JWA, AS), Palo Alto, California.
authors.forename: John
authors.initials: J
authors.lastname: Wesson Ashford
authors.affiliation: Department of Psychiatry and Behavioral Sciences (VD, JWA, AS); Veterans Administration Palo Alto Health Care System (VD, BM, DD, SM, KJM, BL, PN, DP, JWA, AS), Palo Alto, California. Electronic address: asalehi@stanford.edu.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Salehi
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000627:therapeutic use*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003712:Dendrites / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D004314:Down Syndrome / Q000188:drug therapy* / Q000473:pathology; D004983:Ethanolamines / Q000494:pharmacology* / Q000627:therapeutic use*; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D000068759:Formoterol Fumarate; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009248:Nadolol / Q000494:pharmacology; D009474:Neurons / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000319:Adrenergic beta-Antagonists; D000089622:Doublecortin Domain Proteins; D004983:Ethanolamines; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D018343:Receptors, Adrenergic, beta-2; D016708:Synaptophysin; D016222:Fibroblast Growth Factor 2; D009248:Nadolol; D000068759:Formoterol Fumarate
keywords: Alzheimer’s disease; Down syndrome; Ts65Dn; formoterol; locus coeruleus; norepinephrine; β2 adrenergic receptors