Inhibition of Caspases Protects Cerebellar Granule Cells of the Weaver Mouse from Apoptosis and Improves Behavioral Phenotype

The homozygous mouse mutant weaver exhibits a massive loss of cerebellar granule neurons postnatally. The death of these cells is associated with a single amino acid mutation in the G protein-activated inwardly rectifying potassium channel, Girk2. Evidence suggests that both the mutated Girk2 channe...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-11, Vol.277 (46), p.44285-44291
Main Authors: Peng, Jun, Wu, Zhijin, Wu, Yongqin, Hsu, Mike, Stevenson, Fang Feng, Boonplueang, Rapee, Roffler-Tarlov, Suzanne K, Andersen, Julie K
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Behavior, Animal
Caspase 3
Caspase 8
Caspase 9
Caspase Inhibitors
Caspases - metabolism
Cell Adhesion Molecules, Neuronal - metabolism
Cell Survival
Cerebellum - cytology
Contactin 2
Enzyme Activation
G Protein-Coupled Inwardly-Rectifying Potassium Channels
Homozygote
Immunohistochemistry
Mice
Mice, Neurologic Mutants
Microscopy, Fluorescence
Models, Biological
Mutation
Phenotype
Potassium Channels - metabolism
Potassium Channels, Inwardly Rectifying
Protein Structure, Tertiary
Receptors, N-Methyl-D-Aspartate - metabolism
Time Factors
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Summary:The homozygous mouse mutant weaver exhibits a massive loss of cerebellar granule neurons postnatally. The death of these cells is associated with a single amino acid mutation in the G protein-activated inwardly rectifying potassium channel, Girk2. Evidence suggests that both the mutated Girk2 channel and the calcium channel-associated N -methyl- d -aspartate receptor play important roles in the apoptotic death of weaver cerebellar granule cells, but the downstream events associated with this process are unknown. In this study, we demonstrate that the consequences of the mutation result in caspase activation. In addition, our results show that caspase inhibition in vivo decreases caspase activation and granule cell apoptosis and significantly improves behavioral deficits associated with the weaver's phenotype.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M207407200