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

Evidence suggests that neuronal dysfunction in Huntington9s disease (HD) striatum involves deficits in mitochondrial function and in Ca 2+ handling. However, the relationship between mitochondria and Ca 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 2+ and mitochondrial membrane potential to explore the role of in situ HD mitochondria in Ca 2+ handling. Immortalized striatal (ST Hdh ) 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 ST Hdh cells occludes the mitochondrial role in Ca 2+ handling as well as the effects of mitochondrial inhibitors, (2) ST Hdh cells and striatal neurons in the absence of glycolysis are critically dependent on oxidative phosphorylation for energy-dependent Ca 2+ handling, (3) expression of full-length mutant Htt is associated with deficits in mitochondrial-dependent Ca 2+ handling that can be ameliorated by treatment with HDAC inhibitors (treatment with trichostatin A or sodium butyrate decreases the proportion of ST Hdh cells losing Ca 2+ homeostasis after Ca 2+ -ionophore challenging, and accelerates the restoration of intracellular Ca 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 2+ handling, thus improving the neuronal ability to cope with excitotoxic stimuli.