Neuroprotective effects of synaptic modulation in Huntington's disease R6/2 mice.
Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder in which the neostriatum degenerates early and most severely, with involvement of other brain regions. There is significant evidence that excitotoxicity may play a role in striatal degeneration through altered afferent corticostriatal and nigrostriatal projections that may modulate synaptically released striatal glutamate. Glutamate is a central tenant in provoking excitotoxic cell death in striatal neurons already weakened by the collective molecular events occurring in HD. In addition, transcriptional suppression of trophic factors occurs in human and transgenic mouse models of HD, suggesting that a loss of trophic support might contribute to degeneration. Since anti-glutamate approaches have been effective in improving disease phenotype in HD mice, we examined whether deafferentation of the corticostriatal and nigrostriatal pathways may mitigate striatal stress and neurodegeneration. Both surgical and chemical lesions of the corticostriatal and nigrostriatal pathways, respectively, improved the behavioral, neuropathological, and biochemical phenotype in R6/2 transgenic mice and extended survival. Decortication ameliorated hindlimb clasping, striatal neuron atrophy, and huntingtin-positive aggregates, improved N-acetyl aspartate/creatine levels, reduced oxidative stress, and significantly lowered striatal glutamate levels. In addition, 6-hydroxydopamine lesioned mice showed extended survival along with a significant reduction in striatal glutamate. These results suggest that synaptic stress is likely to contribute to neurodegeneration in HD, whereas transsynaptic trophic influences may not be as salient. Thus, modulation of synaptic influences continues to have therapeutic potential in HD.
Stack
Edward C
EC
Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, Massachusetts 01730, USA.
Dedeoglu
Alpaslan
A
Smith
Karen M
KM
Cormier
Kerry
K
Kubilus
James K
JK
Bogdanov
Mikhail
M
Matson
Wayne R
WR
Yang
Lichuan
L
Jenkins
Bruce G
BG
Luthi-Carter
Ruth
R
Kowall
Neil W
NW
Hersch
Steven M
SM
Beal
M Flint
MF
Ferrante
Robert J
RJ
D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D009434:Neural Pathways / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000473:pathology*