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The Journal of Neuroscience, September 15, 2004, 24(37):8153-8160; doi:10.1523/JNEUROSCI.1766-04.2004

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Neurobiology of Disease
Hippocampal Long-Term Potentiation Suppressed by Increased Inhibition in the Ts65Dn Mouse, a Genetic Model of Down Syndrome

Alexander M. Kleschevnikov,¹ Pavel V. Belichenko,¹ Angela J. Villar,³ Charles J. Epstein,³ Robert C. Malenka,² and William C. Mobley¹

¹Department of Neurology and Neurological Sciences, and the Institute for Neuroscience, and ²Nancy Pritzker Laboratory, Department of Psychiatry, Stanford University Medical School, Stanford University, Stanford, California 94305, and ³Department of Pediatrics, University of California, San Francisco, San Francisco, California 94143

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.

Key words: Down syndrome; synaptic; presynaptic; inhibition; long-term potentiation; dentate; gyrus; GABAergic

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Received May 7, 2004; revised July 26, 2004; accepted July 27, 2004.

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