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The Journal of Neuroscience, November 26, 2008, 28(48):12725-12735; doi:10.1523/JNEUROSCI.4619-08.2008

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Neurobiology of Disease
Polyglutamine-Modulated Striatal Calpain Activity in YAC Transgenic Huntington Disease Mouse Model: Impact on NMDA Receptor Function and Toxicity

Catherine M. Cowan,¹ Mannie M. Y. Fan,¹ Jing Fan,² Jacqueline Shehadeh,¹ Lily Y. J. Zhang,¹ Rona K. Graham,³ Michael R. Hayden,³ and Lynn A. Raymond¹

¹Department of Psychiatry and ²Graduate Program in Neuroscience, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3, and ³Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada V5Z 4H4

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

Huntington disease (HD), caused by CAG expansion in the ubiquitously expressed huntingtin gene, is characterized by early dysfunction and death of striatal medium-sized spiny neurons (MSNs). Previous work has shown MSN-specific alterations in NMDA receptor (NMDAR) expression and cell death signaling. Furthermore, studies in HD human brain tissue and a knock-in mouse model demonstrate increases in calpain activity, which can be stimulated by NMDARs and contribute to excitotoxicity. Here, we report increased calpain activity in MSNs from the yeast artificial chromosome (YAC) transgenic mouse model of HD, expressing human full-length huntingtin with 128 polyglutamine repeats (YAC128), compared with wild type. Moreover, the calpain-cleaved product of NMDAR subunit NR2B is increased early, and NR2B expression levels are reduced, in YAC128 striatum. Although steady-state NMDAR surface expression is similar in wild-type and YAC128 MSNs, the rate of loss of NR2B-containing surface receptors is enhanced in YAC128 MSNs, suggesting that NMDAR forward trafficking to the surface is also faster, as previously reported for YAC72 MSNs. Calpain inhibitor-1 treatment normalized the loss rate of surface NMDARs in YAC128 MSNs to that of wild type, and significantly increased surface NMDAR expression in YAC128, but not in wild type or YAC72. With acute NMDAR overstimulation, the increase in calpain activity correlated with polyglutamine length, and calpain inhibitor treatment reduced NMDA-induced apoptosis in YAC72 and YAC128 MSNs to wild-type levels. Thus, the cumulative effect of increasing huntingtin polyglutamine length is to enhance MSN sensitivity to excitotoxicity at least in part by calpain-mediated cell death signaling.

Key words: Huntington; NMDA receptor; calpain; calcium; toxicity; trafficking; striatum

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Received Sept. 23, 2008; accepted Oct. 13, 2008.

Correspondence should be addressed to Dr. Lynn A. Raymond, Department of Psychiatry, University of British Columbia, 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:

				R. K. Graham, M. A. Pouladi, P. Joshi, G. Lu, Y. Deng, N.-P. Wu, B. E. Figueroa, M. Metzler, V. M. Andre, E. J. Slow, et al. Differential Susceptibility to Excitotoxic Stress in YAC128 Mouse Models of Huntington Disease between Initiation and Progression of Disease J. Neurosci., February 18, 2009; 29(7): 2193 - 2204. [Abstract] [Full Text] [PDF]

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