TY - JOUR
T1 - Environmental Enrichment Rescues Protein Deficits in a Mouse Model of Huntington's Disease, Indicating a Possible Disease Mechanism
AU - Spires, Tara L.
AU - Grote, Helen E.
AU - Varshney, Neelash K.
AU - Cordery, Patricia M.
AU - Van Dellen, Anton
AU - Blakemore, Colin
AU - Hannan, Anthony J.
PY - 2004/3/3
Y1 - 2004/3/3
N2 - 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.
AB - 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.
KW - BDNF
KW - DARPP-32
KW - Environmental enrichment
KW - Huntington's disease
KW - NGF
KW - R6/1
KW - Transgenic mouse model
UR - http://www.scopus.com/inward/record.url?scp=1542286877&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.1658-03.2004
DO - 10.1523/JNEUROSCI.1658-03.2004
M3 - Article
C2 - 14999077
AN - SCOPUS:1542286877
VL - 24
SP - 2270
EP - 2276
JO - The Journal of neuroscience : the official journal of the Society for Neuroscience
JF - The Journal of neuroscience : the official journal of the Society for Neuroscience
SN - 0270-6474
IS - 9
ER -