Elsevier

Brain Research

Volume 1140, 6 April 2007, Pages 4-18
Brain Research

Research Report
The Lurcher mouse: Fresh insights from an old mutant

https://doi.org/10.1016/j.brainres.2005.11.086Get rights and content

Abstract

The Lurcher mouse was first discovered in 1954 as a spontaneously occurring autosomal dominant mutation that caused the degeneration of virtually all cerebellar Purkinje cells and most olivary neurons and granule cells. More recent molecular studies revealed that Lurcher is a gain of function mutation in the δ2 glutamate receptor (GluRδ2) that converts an alanine to threonine in the highly conserved third hydrophobic segment of GluRδ2. The mutation converts the receptor into a constitutively leaky cation channel. The GluRδ2 receptor is predominantly expressed in cerebellar Purkinje cells and in the heterozygous Lurcher mutant (+/Lc). Purkinje cells die due to the mutation in the GluRδ2 receptor, while olivary neurons and granule cells degenerate due to the loss of their Purkinje cell targets. The purpose of the review is to provide highlights from 5 decades of research on the Lurcher mutant that have provided insights into the developmental mechanisms that regulate cell number during development, cerebellar pattern formation, cerebellar physiology, and the role of the cerebellum in CNS function.

Introduction

The Lurcher mouse (+/Lc; gene symbol, Grid2Lc) is a neurological mutant characterized by a wobbly, lurching gait which is caused by the extensive postnatal degeneration of key neurons in the olivocerebellar circuit, principally, the Purkinje cells and their primary afferents, granule cells and olivary neurons. The +/Lc mutant was discovered as a spontaneous mutant in the mouse colony of the Medical Research Council Radiobiological Research Unit at Harwell, England in 1954. The first description of the mutant was published in 1960 by R.J.S. Philips (Phillips, 1960). In addition to describing the ataxic characteristics of the Lurcher mutant, Dr. Philips showed that the mutated gene was on chromosome 6 and the mutation was semi-dominant, with homozygous mutants dying around birth. Heterozygous animals are viable, and, since 1960, the +/Lc mutants have provided a fertile source for a large variety of studies aimed at understanding CNS function, from development to behavior. The identification of the gene that is mutated in Lurcher, the δ2 glutamate receptor (GluRδ2; gene symbol, Grid2), in 1997 (Zuo et al., 1997), has inspired a fresh round of studies of the Lurcher mutation that are providing new insights into how the CNS functions, from the molecular biology of glutamate neurotransmitter receptors to the pathways of neuronal cell death and survival. The goal of this review is to highlight the role that the Lurcher mutant has played in a wide array of anatomical, physiological, behavioral, and molecular studies of the CNS, and, hopefully, to indicate promising future research directions that depend on the Lurcher mutant.

Section snippets

Early descriptions of the mutant

Once the +/Lc mutant was identified, initial studies quickly focused on the obvious degeneration of the cerebellum as a primary site of the genetic lesion in the heterozygous +/Lc mutants. The early histological studies determined that, in the adult +/Lc mutants, the cytoarchitecture of the cerebellum was severely disrupted with the loss of virtually all Purkinje cells and the vast majority of the granule cells and olivary neurons (Fig. 1; Caddy and Biscoe, 1975, Caddy and Biscow, 1976, Wilson,

Chimeric analyses of the +/Lc mutant: regulation of neuronal number in the CNS

The qualitative and quantitative descriptions of neuron degeneration and survival in the +/Lc cerebella could not be interpreted with respect to the mechanism of cell death without knowing where the mutant Lurcher gene is acting—the site of gene action. This deficit was addressed by a series of studies by Wetts and Herrup (1982b,c). They analyzed +/Lc ↔ wild-type chimeras and determined that Purkinje cells are a primary site of gene action in the +/Lc mutant, whereas olivary neurons and granule

δ2 glutamate receptors and cerebellar function

The Lurcher mutation was identified as a gain of function in the δ2 glutamate receptor by Zuo et al. (1997). There are two δ glutamate receptors (GluRδ1 and GluRδ2) that were isolated on the basis of their sequence homology to the NMDA and AMPA/kainate receptor subunits (∼20–30% homology; Araki et al., 1993, De Jager and Heintz, 1998, Lomeli et al., 1993, Yamazaki et al., 1992). GluRδ1 expression is relatively low throughout the adult rat CNS, except for high levels in inner hair cells and in

Immuno-endocrinological abnormalities in +/Lc mutant mice

The neurodegeneration in +/Lc mice is accompanied by a chronic inflammatory state, which is evident both at the periphery and in the brain. Stimulation of peritoneal macrophages of +/Lc mice by the active fragment of endotoxin, lipopolysaccharide (LPS), induces higher expression of the proinflammatory cytokines IL-1α, IL-1β, and TNFα at the mRNA and protein levels, compared with wild-type mice while the level of IL-6 remains normal (Kopmels et al., 1990, Kopmels et al., 1991, Vernet-der

The Lurcher mutant as a model system for investigating cerebellar function

As the carrier of a mutation that specifically affects the development of the olivocerebellar circuit, +/Lc mutant mice have proved to be valuable models for investigating not only neuron–target interactions in the developing cerebellum, but larger questions of how the cerebellum interacts with the rest of the nervous system, including its influence on behavior. This section will provide selected examples of the use of the +/Lc mutant to investigate developmental interactions in the cerebellum

Conclusion

In the past 50 years of analysis, the +/Lc mutant has proved to be a valuable model for studying the mechanisms of cerebellar development, cerebellar physiology, and the role of the cerebellum in CNS function. Studies of +/Lc Purkinje cell, granule cell, and olivary neuron cell death have contributed insights into the developmental mechanisms that regulate cell number in the CNS. The behavioral studies in the +/Lc mutant have emphasized that the cerebellum plays a larger role in CNS function

Acknowledgments

Supported by NIH Grant NS34309 (MWV and JM) and a grant-in-aid from the Ministry of Education, Science, Sports and Culture of Japan (MY). The authors acknowledge the contributions of their collaborators involved in the production of the results described in this review.

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