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Article Dans Une Revue FASEB Journal Année : 2006

Brain mitochondrial defects amplify intracellular [Ca2+] rise and neurodegeneration but not Ca2+ entry during NMDA receptor activation

Résumé

According to the "indirect" excitotoxicity hypothesis, mitochondrial defects increase Ca2+ entry into neurons by rendering NMDA-R hypersensitive to glutamate. We tested this hypothesis by investigating in the rat striatum and cultured striatal cells how partial mitochondrial complex II inhibition produced by 3-nitropropionic acid (3NP) modifies the toxicity of the NMDA-R agonist quinolinate (QA). We showed that nontoxic 3NP treatment, leading to partial inhibition of complex II activity, greatly exacerbated striatal degeneration produced by slightly toxic QA treatment through an "all-or-nothing" process. The potentiation of QA-induced cell death by 3NP was associated with increased calpain activity and massive calpain-mediated cleavage of several postsynaptic proteins, suggesting major neuronal Ca2+ deregulation in the striatum. However, Ca2+ anomalies probably do not result from NMDA-R hypersensitivity. Indeed, brain imaging experiments using [18F]fluorodeoxyglucose indirectly showed that 3NP did not increase QA-induced ionic perturbations at the striatal glutamatergic synapses in vivo. Consistent with this, the exacerbation of QA toxicity by 3NP was not related to an increase in the QA-induced entry of 45Ca2+ into striatal neurons. The present results demonstrate that the potentiation of NMDA-R-mediated excitotoxicity by mitochondrial defects involves primarily intracellular Ca2+ deregulation, in the absence of NMDA-R hypersensitivity.

Domaines

Neurobiologie
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Dates et versions

hal-00103460 , version 1 (04-10-2006)

Identifiants

Citer

Carine Jacquard, Yael Trioulier, François Cosker, Carole Escartin, Nicolas Bizat, et al.. Brain mitochondrial defects amplify intracellular [Ca2+] rise and neurodegeneration but not Ca2+ entry during NMDA receptor activation. FASEB Journal, 2006, 20(7), pp.1021-1023. ⟨10.1096/fj.05-5085fje⟩. ⟨hal-00103460⟩
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