Mitochondrial defects and abnormal glutamatergic transmission (excitotoxicity) are the main mechanisms potentially involved in chronic neurodegenerative disorders, like Alzheimers' disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis and acute neurological diseases, like ischemia. Huntington's disease is characterised by a striatal neurodegenerescence associated with a decrease in mitochondrial complex II activity. Mechanisms of cell death induced by the inhibition of the complex II are unknown in vivo and we have characterised them in rat model with toxic admistration of 3-nitropropionic acid (3-NP). Calpain is the major protease responsible for the neurodegenerescence in the striatum in parallel to an activation of caspases. Moreover, transgenic mouse models of Huntington's disease present hyperactivity of NMDA receptors. Mitochondrial defects could potentiate the toxicity of NMDA-R activation but the mechanisms of this potentiation are unknown in vivo.The aim of the present study was to investigate the mechanisms underlaying the potentiation of NMDA-R mediated neurodegeneration by chronic mitochondrial dysfunction. We determined how the toxicity of the NMDA-R agonist, quinolinate was amplified by chronic administration of 3-NP. Potentiation of cell death by the 3-NP occurs for inhibition of complex II higher than 35%. 3-NP alone produced striatal lesion for inhibition of complex II higher than 50%. Between 35 and 50%, cell death in the striatum is potentiated by a factor 10. This potentiation implies calcium deregulation seen by the cytosolic activation of calpain. The calcium deregulation is not consecutive from a hyperactivation of NMDA-R because striatal glucosis uptake induced by quinolinate is not modified by 3-NP. In complement, calcium entry in primary striatal cells induced by quinolinate is not increased by 3-NP although cytosolic calcium is increased, as seen by calcium imaging. These results show that potentiation implies calcium deregulation, leading to calpain activation in absence of NMDA-R hypersensitivity. These in vivo results provide support for the view that mitochondrial defects and NMDA-R activation may have synergistic effects in neurodegenerative disorders, like Huntington's disease and that calcium homeostasis constitute a therapeutic target.
