Mitochondrial-Dependent Ca super(2+) Handling in Huntington's Disease Striatal Cells: Effect of Histone Deacetylase Inhibitors

• Published in: The Journal of neuroscience 2006-10, Vol.26 (43), p.11174-11186
• Main Authors: Oliveira, Jorge MA, Chen, Sylvia, Almeida, Sandra, Riley, Rebeccah, Goncalves, Jorge, Oliveira, Catarina R, Hayden, Michael R, Nicholls, David G, Ellerby, Lisa M, Rego, ACristina
• Format: Article
• Language: English
• ISSN: 0270-6474; 1529-2401

Evidence suggests that neuronal dysfunction in Huntington's disease (HD) striatum involves deficits in mitochondrial function and in Ca super(2+) handling. However, the relationship between mitochondria and Ca super(2+) 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 Ca super(2+) and mitochondrial membrane potential to explore the role of in situ HD mitochondria in Ca super(2+) 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 Ca super(2+) 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 Ca super(2+) handling, (3) expression of full-length mutant Htt is associated with deficits in mitochondrial-dependent Ca super(2+) handling that can be ameliorated by treatment with HDAC inhibitors (treatment with trichostatin A or sodium butyrate decreases the proportion of STHdh cells losing Ca super(2+) homeostasis after Ca super(2+)-ionophore challenging, and accelerates the restoration of intracellular Ca super(2+) 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 Ca super(2+) handling, thus improving the neuronal ability to cope with excitotoxic stimuli.