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The Journal of Neuroscience, December 12, 2007, 27(50):13614-13623; doi:10.1523/JNEUROSCI.3455-07.2007

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Neurobiology of Disease
Mitochondrial Sensitivity and Altered Calcium Handling Underlie Enhanced NMDA-Induced Apoptosis in YAC128 Model of Huntington's Disease

Herman B. Fernandes,^1,3 Kenneth G. Baimbridge,² John Church,² Michael R. Hayden,^3,4,5 and Lynn A. Raymond^1,3

Departments of ¹Psychiatry and ²Cellular and Physiological Sciences and ³Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3, and ⁴Department of Medical Genetics and ⁵Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4

Correspondence should be addressed to Dr. Lynn A. Raymond, University of British Columbia, Department of Psychiatry, Room 4834-2255 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 1Z3. Email: lynnr{at}interchange.ubc.ca

Expansion of a CAG repeat in the Huntington's disease (HD) gene results in progressive neuronal loss, particularly of striatal medium-sized spiny neurons (MSNs). Studies in human HD autopsy brain tissue, as well as cellular and animal models of HD, suggest that increased activity of NMDA-type glutamate receptors and altered mitochondrial function contribute to selective neuronal degeneration. In this regard, the YAC128 mouse model, expressing full-length human huntingtin with 128 glutamine repeats, has been the focus of much interest. Although NMDA-induced apoptosis is enhanced in YAC128 MSNs, here we report that the initial steps in the death signaling pathway, including NMDA receptor (NMDAR) current and cytosolic Ca²⁺ loading, are similar to those observed in wild-type MSNs. In contrast, we found that the NMDAR-mediated Ca²⁺ load triggered a strikingly enhanced loss of mitochondrial membrane potential in YAC128 MSNs, suggesting that NMDAR signaling via the mitochondrial apoptotic pathway is altered. This effect was accompanied by impaired cytosolic Ca²⁺ clearance after removal of NMDA, a difference that was not apparent after high potassium-evoked depolarization-mediated Ca²⁺ entry. Inhibition of the mitochondrial permeability transition (mPT) reduced peak cytosolic Ca²⁺ and mitochondrial depolarization evoked by NMDA in YAC128 MSNs but not wild-type MSNs. Hence, in contrast to YAC models with moderate CAG expansions, the enhanced NMDA-induced apoptosis in YAC128 MSNs is predominantly determined by augmented mitochondrial sensitivity to Ca²⁺-induced activation of the mPT. These results suggest that the CAG repeat length influences the mechanism by which mHtt enhances NMDAR-mediated excitotoxicity.

Key words: mutant huntingtin; NMDA receptor; calcium; mitochondria; ratiometric imaging; striatal neurons

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Received March 27, 2007; revised Sept. 18, 2007; accepted Sept. 20, 2007.

Correspondence should be addressed to Dr. Lynn A. Raymond, University of British Columbia, Department of Psychiatry, Room 4834-2255 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 1Z3. Email: lynnr{at}interchange.ubc.ca

This article has been cited by other articles:

				C. M. Cowan, M. M. Y. Fan, J. Fan, J. Shehadeh, L. Y. J. Zhang, R. K. Graham, M. R. Hayden, and L. A. Raymond Polyglutamine-Modulated Striatal Calpain Activity in YAC Transgenic Huntington Disease Mouse Model: Impact on NMDA Receptor Function and Toxicity J. Neurosci., November 26, 2008; 28(48): 12725 - 12735. [Abstract] [Full Text] [PDF]

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