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The Journal of Neuroscience, November 21, 2007, 27(47):12908-12915; doi:10.1523/JNEUROSCI.4318-07.2007

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Neurobiology of Disease
Neuroprotective Effects of Synaptic Modulation in Huntington's Disease R6/2 Mice

Edward C. Stack,^1,2 Alpaslan Dedeoglu,^1,2,8 Karen M. Smith,^1,2 Kerry Cormier,¹ James K. Kubilus,² Mikhail Bogdanov,⁴ Wayne R. Matson,¹ Lichuan Yang,⁴ Bruce G. Jenkins,^8,9 Ruth Luthi-Carter,^5,6 Neil W. Kowall,^1,2 Steven M. Hersch,^5,7 M. Flint Beal,⁴ and Robert J. Ferrante^1,2,3

¹Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, Massachusetts 01730, ²Departments of Neurology and ³Pathology and Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02118, ⁴Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, New York 10021, ⁵Massachusetts General Institute of Neurodegenerative Disease, Charlestown, Massachusetts 02129, ⁶Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland, and Departments of ⁷Neurology, ⁸Radiology, and ⁹Physics, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Correspondence should be addressed to Dr. Robert J. Ferrante, Geriatric Research Education and Clinical Center Unit 182B, Bedford Veterans Administration Medical Center, 200 Springs Road, Bedford, MA 01730. Email: rjferr{at}bu.edu

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.

Key words: glutamate; dopamine; deafferentation; 6-OHDA; excitotoxicity; Huntington's disease

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Received Aug. 21, 2007; accepted Oct. 8, 2007.

Correspondence should be addressed to Dr. Robert J. Ferrante, Geriatric Research Education and Clinical Center Unit 182B, Bedford Veterans Administration Medical Center, 200 Springs Road, Bedford, MA 01730. Email: rjferr{at}bu.edu

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