Mechanisms of Compartmental Purkinje Cell Death and Survival in the Lurcher Mutant Mouse

The Lurcher mutant mouse is characterized by its ataxic gait and loss of cerebellar Purkinje cells and their afferents, granule cells and olivary neurons, during the first weeks of postnatal development. For the 50 years since its discovery, the heterozygous Lurcher mutant has served as an important model system for studying neuron-target interactions in the developing cerebellum and cerebellar function. The identification of the Lurcher (Lc) gene over 10 years ago as a gain-of-function mutation in the delta 2 glutamate receptor (GluR delta 2) led to extensive studies of cell death mechanisms in the Lc/+ cerebellum. The advantage of this model system is that GluR delta 2(+) receptors and GluR delta 2 (Lc) channels are expressed predominantly in Purkinje cells, making it possible to study the effects of a well-characterized leak current in a well-defined cell type during a critical phase of neuronal development. Yet there is still controversy surrounding the mechanisms of neuronal death in Lc/+ Purkinje cells with competing hypotheses for necrotic, apoptotic, and autophagic cell death pathways as a consequence of the excitotoxic stress caused by the GluR delta 2 (Lc) leak current. The goal of this review is to summarize recent studies that critically test the role of various cell death pathways in Lc/+ Purkinje cell degeneration with respect to evidence for the molecular heterogeneity of Purkinje cells. We propose that the expression of putative survival factors, such as heat shock proteins, in a subset of cerebellar Purkinje cells may affect cell death pathways and account for the pattern and diverse mechanisms of Lc/+ Purkinje degeneration.