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The Journal of Neuroscience, April 18, 2007, 27(16):4424-4434; doi:10.1523/JNEUROSCI.5113-06.2007

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Neurobiology of Disease
Brain-Derived Neurotrophic Factor Restores Synaptic Plasticity in a Knock-In Mouse Model of Huntington's Disease

Gary Lynch,¹ Eniko A. Kramar,¹ Christopher S. Rex,² Yousheng Jia,¹ Danielle Chappas,¹ Christine M. Gall,^2,3 and Danielle A. Simmons¹

Departments of ¹Psychiatry and Human Behavior, ²Neurobiology and Behavior, and ³Anatomy and Neurobiology, University of California, Irvine, California 92617-4291

Correspondence should be addressed to Dr. Danielle A. Simmons, 101 Theory Drive, Suite 250, University of California, Irvine, CA 92612-1695. Email: simmonsd{at}uci.edu

Asymptomatic Huntington's disease (HD) patients exhibit memory and cognition deficits that generally worsen with age. Similarly, long-term potentiation (LTP), a form of synaptic plasticity involved in memory encoding, is impaired in HD mouse models well before motor disturbances occur. The reasons why LTP deteriorates are unknown. Here we show that LTP is impaired in hippocampal slices from presymptomatic Hdh^Q92 and Hdh^Q111 knock-in mice, describe two factors contributing to this deficit, and establish that potentiation can be rescued with brain-derived neurotrophic factor (BDNF). Baseline physiological measures were unaffected by the HD mutation, but LTP induction and, to a greater degree, consolidation were both defective. The facilitation of burst responses that normally occurs during a theta stimulation train was reduced in HD knock-in mice, as was theta-induced actin polymerization in dendritic spines. The decrease in actin polymerization and deficits in LTP stabilization were reversed by BDNF, concentrations of which were substantially reduced in hippocampus of both Hdh^Q92 and Hdh^Q111 mice. These results suggest that the HD mutation discretely disrupts processes needed to both induce and stabilize LTP, with the latter effect likely arising from reduced BDNF expression. That BDNF rescues LTP in HD knock-in mice suggests the possibility of treating cognitive deficits in asymptomatic HD gene carriers by upregulating production of the neurotrophin.

Key words: neurotrophin; long-term potentiation; polyglutamine; hippocampus; actin; dendritic spines

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Received Sept. 29, 2006; revised March 6, 2007; accepted March 8, 2007.

Correspondence should be addressed to Dr. Danielle A. Simmons, 101 Theory Drive, Suite 250, University of California, Irvine, CA 92612-1695. Email: simmonsd{at}uci.edu

This article has been cited by other articles:

				A. J. Milnerwood and L. A. Raymond Corticostriatal synaptic function in mouse models of Huntington's disease: early effects of huntingtin repeat length and protein load J. Physiol., December 15, 2007; 585(3): 817 - 831. [Abstract] [Full Text] [PDF]

				J. C. Lauterborn, C. S. Rex, E. Kramar, L. Y. Chen, V. Pandyarajan, G. Lynch, and C. M. Gall Brain-Derived Neurotrophic Factor Rescues Synaptic Plasticity in a Mouse Model of Fragile X Syndrome J. Neurosci., October 3, 2007; 27(40): 10685 - 10694. [Abstract] [Full Text] [PDF]

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