The Lurcher Mutation and Ionotropic Glutamate Receptors: Contributions to Programmed Neuronal Death In vivo

The recent positional cloning and physiological characterization of the lurcher mutation resulted in the identification of a novel stimulus that results in neurodegeneration. The catastrophic loss of cerebellar Purkinje cells in lurcher heterozygotes has now been strongly associated with a large constitutive inward current which ultimately activates a programmed form of neuronal death. The completely penetrant and focal nature of the lurcher phenotype gives us an opportunity to investigate the manner in which neurons respond to an aberrant signal in the context of the brain parenchyma. Although there is no human genetic disease that is equivalent to the lurcher mutation at this time, its triggering of programmed neuronal death enables us to pose and address questions that are relevant to a large number of human neurological diseases. The advantage of working in a genetically manipulable in vivo mammalian system is evident: we can address questions relating to gene function in the nervous system in a context that is physiological. Classical genetic analyses looking for molecules that suppress or modify the lurcher phenotype are under way and have now been supplemented with two novel techniques developed in our laboratory: biolistic transfection of cerebellar slices and Bacterial Artificial Chromosome modification. The integration of these novel and classical approaches will facilitate the testing of hypotheses, developed during the course of our study of the lurcher mutation, which explore the propagation of abnormal signals and the initiation of programmed neuronal death in neurons.