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The Journal of Neuroscience, February 1, 2000, 20(3):992-1000

Target-Related and Intrinsic Neuronal Death in Lurcher Mutant Mice Are Both Mediated by Caspase-3 Activation

Fekrije Selimi, Martin Doughty, Nicole Delhaye-Bouchaud, and Jean Mariani

Laboratoire Développement et Vieillissement du Système Nerveux, Institut des Neurosciences, Unité Mixte de Recherche 7624, Centre National de la Recherche Scientifique et Université Pierre et Marie Curie, 75005 Paris, France

The Lurcher (Lc) mutation in the 2 glutamate receptor gene leads to the presence of a constitutive inward current in the cerebellar Purkinje cells of Lurcher heterozygous mice and to the postnatal degeneration of these neurons. In addition, cerebellar granule cells and olivary neurons of Lc/+ mice die as an indirect effect of the mutation after the loss of their target Purkinje cells. The apoptotic nature of Lc/+ Purkinje cell death remains controversial. To address this question, we studied the involvement of caspase-3, a key effector of apoptosis, in the neurodegenerative processes occurring in Lc/+ cerebellum. Several antibodies recognizing different regions of caspase-3 were used in immunoblotting and immunohistochemical experiments. We demonstrate that pro-caspase-3 is specifically upregulated in the dying Lc/+ Purkinje cells, but not in granule cells and olivary neurons, suggesting that different death-inducing signals trigger variant apoptotic pathways in the CNS. The subcellular localization of pro-caspase-3 was shown to be cytoplasmic and mitochondrial. Active caspase-3 as well as DNA fragmentation was found in numerous granule cells and some Purkinje cells of the Lc/+ cerebellum. Thus, caspase-3 activation is involved in both the direct and indirect neuronal death induced by the Lurcher mutation, strongly supporting the idea that the Lc/+ Purkinje cell dies by apoptosis.

Key words: caspase-3; neuronal death; Lurcher; Purkinje cells; apoptosis; TUNEL; immunohistochemistry

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Copyright © 2000 Society for Neuroscience  0270-6474/00/203992-09$05.00/0

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