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

Carine Jacquard^*, Yael Trioulier^*, François Cosker, Carole Escartin^*, Nicolas Bizat^*, Philippe Hantraye^*, José Manuel Cancela, Gilles Bonvento^* and Emmanuel Brouillet^*,1

^* Unité de Recherche Associée CEA-CNRS 2210, Service Hospitalier Frédéric Joliot, Département de Recherches Médicales, Direction des Sciences du Vivant, Commissariat à l’Energie Atomique, Orsay, France; and

Laboratoire de Neurobiologie cellulaire et moléculaire, CNRS, UPR 9040, Gif-sur-Yvette, France

¹Correspondence: URA CEA-CNRS 2210, Service Hospitalier Frédéric Joliot, DRM, DSV, CEA, 4 place du Général Leclerc, 91401 Orsay cedex, France. Email: brouille{at}shfj.cea.fr

ABSTRACT

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.—Jacquard, C., Trioulier, Y., Cosker, F., Escartin, C., Bizat, N., Hantraye, P., Cancela*, J. M., Bonvento, G., Brouillet, E. Brain mitochondrial defects amplify intracellular [Ca²⁺] rise and neurodegeneration but not Ca²⁺ entry during NMDA receptor activation.

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