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The Journal of Neuroscience, March 3, 2004, 24(9):2270-2276; doi:10.1523/JNEUROSCI.1658-03.2004
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Development/Plasticity/Repair
Environmental Enrichment Rescues Protein Deficits in a Mouse Model of Huntington's Disease, Indicating a Possible Disease Mechanism
Tara L. Spires, Helen E. Grote, Neelash K. Varshney, Patricia M. Cordery, Anton van Dellen, Colin Blakemore, andAnthony J. Hannan University Laboratory of Physiology, University of Oxford, Oxford OX1 3PT, United Kingdom
Huntington's disease (HD) is a devastating neurodegenerative disorder caused by a CAG repeat expansion encoding an extended polyglutamine tract in the huntingtin protein. Transgenic mice expressing a human huntingtin transgene containing an expanded CAG repeat (R6/1 model) develop a neurodegenerative disorder closely resembling human HD. Previous work demonstrated that environmental enrichment delays the onset of motor symptoms in this mouse model. We confirmed that at 5 months of age, enrichment ameliorates motor symptoms (assessed using the rotarod test) and prevents loss of body weight induced by the HD transgene. We further examined molecular consequences of enrichment by determining changes in protein levels in the neostriatum, hippocampus, and anterior cortex using quantitative Western blot analysis. Non-enriched HD mice have severe reductions in BDNF in the hippocampus and striatum at 5 months, which are entirely rescued by enrichment. BDNF levels are unaltered by HD in the anterior cortex, suggesting that enrichment might prevent HD-induced impairment of anterograde transport of this neurotrophin to the striatum. NGF is unaffected by HD. Non-enriched HD mice also exhibit deficits in dopamine and cAMP-regulated phosphoprotein (32 kDa) in striatum and anterior cortex. Environmental enrichment rescues the cortical but not the striatal deficit at 5 months. These results suggest that environmental enrichment benefits animals at early stages of the disease by rescuing protein deficits, possibly through rescuing transcription or protein transport problems.
Key words: Huntington's disease; environmental enrichment; BDNF; DARPP-32; transgenic mouse model; R6/1; NGF
Received Aug 20, 2003; revised January 12, 2004; accepted January 20, 2004.
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