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The Journal of Neuroscience, October 25, 2006, 26(43):11174-11186; doi:10.1523/JNEUROSCI.3004-06.2006

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Neurobiology of Disease
Mitochondrial-Dependent Ca²⁺ Handling in Huntington's Disease Striatal Cells: Effect of Histone Deacetylase Inhibitors

Jorge M. A. Oliveira,^1,2,4 Sylvia Chen,² Sandra Almeida,⁴ Rebeccah Riley,² Jorge Gonçalves,¹ Catarina R. Oliveira,⁴ Michael R. Hayden,³ David G. Nicholls,² Lisa M. Ellerby,² and A. Cristina Rego⁴

¹Serviço de Farmacologia da Faculdade de Farmácia, Centro de Estudos de Química Orgânica, Fitoquímica e Farmacologia, Universidade do Porto, 4050-047 Porto, Portugal, ²Buck Institute for Age Research, Novato, California 94945, ³Department of Medical Genetics, Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4, and ⁴Center for Neuroscience and Cell Biology and Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal

Correspondence should be addressed to Prof. A. Cristina Rego Institute of Biochemistry, Faculty of Medicine, Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal. Email: acrego{at}cnc.cj.uc.pt

Evidence suggests that neuronal dysfunction in Huntington's disease (HD) striatum involves deficits in mitochondrial function and in Ca²⁺ handling. However, the relationship between mitochondria and Ca²⁺ handling has been incompletely studied in intact HD striatal cells. Treatment with histone deacetylase (HDAC) inhibitors reduces cell death in HD models, but the effects of this promising therapy on cellular function are mostly unknown. Here, we use real-time functional imaging of intracellular Ca²⁺ and mitochondrial membrane potential to explore the role of in situ HD mitochondria in Ca²⁺ handling. Immortalized striatal (STHdh) cells and striatal neurons from transgenic mice, expressing full-length mutant huntingtin (Htt), were used to model HD. We show that (1) active glycolysis in STHdh cells occludes the mitochondrial role in Ca²⁺ handling as well as the effects of mitochondrial inhibitors, (2) STHdh cells and striatal neurons in the absence of glycolysis are critically dependent on oxidative phosphorylation for energy-dependent Ca²⁺ handling, (3) expression of full-length mutant Htt is associated with deficits in mitochondrial-dependent Ca²⁺ handling that can be ameliorated by treatment with HDAC inhibitors (treatment with trichostatin A or sodium butyrate decreases the proportion of STHdh cells losing Ca²⁺ homeostasis after Ca²⁺-ionophore challenging, and accelerates the restoration of intracellular Ca²⁺ in striatal neurons challenged with NMDA), and (4) neurons with different response patterns to NMDA receptor activation exhibit different average somatic areas and are differentially affected by treatment with HDAC inhibitors, suggesting subpopulation or functional state specificity. These findings indicate that neuroprotection induced by HDAC inhibitors involves more efficient Ca²⁺ handling, thus improving the neuronal ability to cope with excitotoxic stimuli.

Key words: Huntington's disease; striatal neurons; excitotoxicity; mitochondria; calcium; HDAC inhibitors

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Received Aug. 12, 2005; accepted Aug. 29, 2006.

Correspondence should be addressed to Prof. A. Cristina Rego Institute of Biochemistry, Faculty of Medicine, Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal. Email: acrego{at}cnc.cj.uc.pt

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