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Hippocampal long-term potentiation suppressed by
increased inhibition in the Ts65Dn mouse, a genetic model
of Down syndrome.
Kleschevnikov AM, Belichenko PV, Villar AJ, Epstein CJ, Malenka
RC, Mobley WC.
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
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.
PMID: 15371516 [PubMed - indexed for MEDLINE]
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