Huntington disease (HD) is a fatal neurodegenerative disease with no effective treatment. In the R6/1 mouse model of HD, environmental enrichment delays the neurologic phenotype onset and prevents cere- bral volume loss by unknown molecular mechanisms. We examined the effects of environmental enrichment on well-characterized neuro- pathological parameters in a mouse model of HD. We found a trend toward preservation of downregulated neurotransmitter receptors in striatum of environmentally enriched mice and assessed possible enrichment-related modifications in gene expression using micro- arrays. We observed similar gene expression changes in R6/1 and R6/2 transgenic mice but found no specific changes in enrichment- related microarray expression profiles in either transgenic or wild-type mice. Furthermore, specific corrections in transprotein-induced tran- scriptional dysregulation in R6/1 mice were not detected by microarray profiling. However, gene-specific analyses suggested that long-term environmental enrichment may beneficially modulate gene expres- sion dysregulation. Finally, environmental enrichment significantly decreased neuronal intranuclear inclusion load, despite unaffected transgene expression levels. Thus, the therapeutic effects of environmental enrichment likely contribute to decreasing aggregated polyglutamine protein levels without exerting strong effects on gene expression.

Caroline L. Benn, PhD, Ruth Luthi-Carter, PhD, Alexandre Kuhn, PhD, Ghazaleh Sadri-Vakili, PhD, Kwabena L. Blankson, MA, MD, Sudeb C. Dalai, MSc, Darlene R. Goldstein, PhD, Tara L. Spires, PhD, Joel Pritchard, MSc, James M. Olson, MD, PhD, Anton van Dellen, PhD, Anthony J. Hannan, PhD, and Jang-Ho J. Cha, MD, PhD

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