Neurodegeneration inLurcherMice Occurs via Multiple Cell Death Pathways

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Abstract
Lurcher (Lc) is a gain-of-function mutation in the δ2 glutamate receptor (GRID2) that results in the cell-autonomous death of cerebellar Purkinje cells in heterozygouslurcher (+/Lc) mice. This in turn triggers the massive loss of afferent granule cells during the first few postnatal weeks. Evidence suggests that the death of Purkinje cells as a direct consequence of GRID2Lc activation and the secondary death of granule cells because of target deprivation occur by apoptosis. We have used mice carryingnull mutations of both the Bax andp53 genes to examine the roles of these genes in cell loss in lurcher animals. The absence ofBax delayed Purkinje cell death in response to theGRID2Lc mutation and permanently rescued the secondary death of granule cells. In contrast, thep53 deletion had no effect on either cell death pathway. Our results demonstrate that target deprivation induces aBax-dependent, p53-independent cell death response in cerebellar granule cells in vivo. In contrast, Bax plays a minor role in GRID2Lc-mediated Purkinje cell death.