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, Anthony J. Hannan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

291 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2270-2276
Number of pages7
JournalJournal of Neuroscience
Volume24
Issue number9
DOIs
Publication statusPublished - 3 Mar 2004
Externally publishedYes

Keywords

  • BDNF
  • DARPP-32
  • Environmental enrichment
  • Huntington's disease
  • NGF
  • R6/1
  • Transgenic mouse model

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