title: Hedgehog agonist therapy corrects structural and cognitive deficits in a Down syndrome mouse model.
abstract: Down syndrome (DS) is among the most frequent genetic causes of intellectual disability, and ameliorating this deficit is a major goal in support of people with trisomy 21. The Ts65Dn mouse recapitulates some major brain structural and behavioral phenotypes of DS, including reduced size and cellularity of the cerebellum and learning deficits associated with the hippocampus. We show that a single treatment of newborn mice with the Sonic hedgehog pathway agonist SAG 1.1 (SAG) results in normal cerebellar morphology in adults. Further, SAG treatment at birth rescued phenotypes associated with hippocampal deficits that occur in untreated adult Ts65Dn mice. This treatment resulted in behavioral improvements and normalized performance in the Morris water maze task for learning and memory. SAG treatment also produced physiological effects and partially rescued both N-methyl-d-aspartate (NMDA) receptor-dependent synaptic plasticity and NMDA/AMPA receptor ratio, physiological measures associated with memory. These outcomes confirm an important role for the hedgehog pathway in cerebellar development and raise the possibility for its direct influence in hippocampal function. The positive results from this approach suggest a possible direction for therapeutic intervention to improve cognitive function for this population.
authors.affiliation: Department of Physiology and Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Ishita
authors.initials: I
authors.lastname: Das
authors.forename: Joo-Min
authors.initials: JM
authors.lastname: Park
authors.forename: Jung H
authors.initials: JH
authors.lastname: Shin
authors.forename: Soo Kyeong
authors.initials: SK
authors.lastname: Jeon
authors.forename: Hernan
authors.initials: H
authors.lastname: Lorenzi
authors.forename: David J
authors.initials: DJ
authors.lastname: Linden
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
authors.forename: Roger H
authors.initials: RH
authors.lastname: Reeves
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002531:Cerebellum / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy; D003514:Cyclohexylamines / Q000737:chemistry*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000188:drug therapy*; D004594:Electrophysiology / Q000379:methods; D053823:Hedgehog Proteins / Q000819:agonists* / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D036881:Long-Term Synaptic Depression; D008297:Male; D018782:Maze Learning; D008568:Memory / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity; D010641:Phenotype; D011689:Purkinje Cells / Q000166:cytology; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D009435:Synaptic Transmission; D013876:Thiophenes / Q000737:chemistry*
chemical_list: D003514:Cyclohexylamines; D053823:Hedgehog Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C468918:SAG compound; D013876:Thiophenes