title: Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome.
abstract: Although many genetic disorders are characterized by cognitive failure during development, there is little insight into the neurobiological basis for the abnormalities. Down syndrome (DS), a disorder caused by the presence of three copies of chromosome 21 (trisomy 21), is characterized by impairments in learning and memory attributable to dysfunction of the hippocampus. We explored the cellular basis for these abnormalities in Ts65Dn mice, a genetic model for DS. Although basal synaptic transmission in the dentate gyrus was normal, there was severe impairment of long-term potentiation (LTP) as a result of reduced activation of NMDA receptors. After suppressing inhibition with picrotoxin, a GABA(A) receptor antagonist, NMDA receptor-mediated currents were normalized and induction of LTP was restored. Several lines of evidence suggest that inhibition in the Ts65Dn dentate gyrus was enhanced, at least in part, because of presynaptic abnormalities. These findings raise the possibility that similar changes contribute to abnormalities in learning and memory in people with DS and, perhaps, in other developmental disorders with cognitive failure.
authors.affiliation: Department of Neurology and Neurological Sciences, and the Institute for Neuroscience, Stanford University Medical School, Stanford University, Stanford, California 94305-5489, USA. akleschevnikov@stanford.edu
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Kleschevnikov
authors.forename: Pavel V
authors.initials: PV
authors.lastname: Belichenko
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Villar
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Epstein
authors.forename: Robert C
authors.initials: RC
authors.lastname: Malenka
authors.forename: William C
authors.initials: WC
authors.lastname: Mobley
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D003072:Cognition Disorders / Q000209:etiology / Q000503:physiopathology; D003433:Crosses, Genetic; D018891:Dentate Gyrus / Q000503:physiopathology; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000503:physiopathology*; D005071:Evoked Potentials; D005260:Female; D058787:GABA-A Receptor Antagonists; D018628:Gene Dosage; D005998:Glycine / Q000494:pharmacology; D006624:Hippocampus / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000502:physiology*; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013045:Species Specificity; D014314:Trisomy
chemical_list: D015763:2-Amino-5-phosphonovalerate; D058787:GABA-A Receptor Antagonists; D005998:Glycine; D008274:Magnesium; D010852:Picrotoxin; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline