title: Deficits in cognition and synaptic plasticity in a mouse model of Down syndrome ameliorated by GABAB receptor antagonists.
abstract: Cognitive impairment in Down syndrome (DS) is characterized by deficient learning and memory. Mouse genetic models of DS exhibit impaired cognition in hippocampally mediated behavioral tasks and reduced synaptic plasticity of hippocampal pathways. Enhanced efficiency of GABAergic neurotransmission was implicated in those changes. We have recently shown that signaling through postsynaptic GABA(B) receptors is significantly increased in the dentate gyrus of Ts65Dn mice, a genetic model of DS. Here we examined a role for GABA(B) receptors in cognitive deficits in DS by defining the effect of selective GABA(B) receptor antagonists on behavior and synaptic plasticity of adult Ts65Dn mice. Treatment with the GABA(B) receptor antagonist CGP55845 restored memory of Ts65Dn mice in the novel place recognition, novel object recognition, and contextual fear conditioning tasks, but did not affect locomotion and performance in T-maze. The treatment increased hippocampal levels of brain-derived neurotrophic factor, equally in 2N and Ts65Dn mice. In hippocampal slices, treatment with the GABA(B) receptor antagonists CGP55845 or CGP52432 enhanced long-term potentiation (LTP) in the Ts65Dn DG. The enhancement of LTP was accompanied by an increase in the NMDA receptor-mediated component of the tetanus-evoked responses. These findings are evidence for a contribution of GABA(B) receptors to changes in hippocampal-based cognition in the Ts65Dn mouse. The ability to rescue cognitive performance through treatment with selective GABA(B) receptor antagonists motivates studies to further explore the therapeutic potential of these compounds in people with DS.
authors: Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA. akleschevnikov@yahoo.com
authors: Alexander M
authors: AM
authors: Kleschevnikov
authors: Pavel V
authors: PV
authors: Belichenko
authors: Mehrdad
authors: M
authors: Faizi
authors: Lucia F
authors: LF
authors: Jacobs
authors: Khin
authors: K
authors: Htun
authors: Mehrdad
authors: M
authors: Shamloo
authors: William C
authors: WC
authors: Mobley
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D058788:GABA-B Receptor Antagonists / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000235:genetics; D009924:Organ Culture Techniques; D009435:Synaptic Transmission / Q000187:drug effects* / Q000235:genetics
chemical_list: D058788:GABA-B Receptor Antagonists