THE LURCHER MUTATION AND IONOTROPIC GLUTAMATE RECEPTORS - CONTRIBUTIONS TO PROGRAMMED NEURONAL DEATH IN-VIVO

The recent positional cloning and physiological characterization of th e 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 associa ted with a large constitutive inward current which ultimately activate s a programmed form of neuronal death. The completely penetrant and fo cal nature of the lurcher phenotype gives us an opportunity to investi gate the manner in which neurons respond to an aberrant signal in the context of the brain parenchyma, Although there is no human genetic di sease that is equivalent to the lurcher mutation at this time, its tri ggering of programmed neuronal death enables us to pose and address qu estions that are relevant to a large number of human neurological dise ases, The advantage of working in a genetically manipulable in vivo ma mmalian system is evident: we can address questions relating to gene f unction in the nervous system in a context that is physiological. Clas sical genetic analyses looking for molecules that suppress or modify t he lurcher phenotype are under way and have now been supplemented with two novel techniques developed in our laboratory: biolistic transfect ion of cerebellar slices and Bacterial Artificial Chromosome modificat ion, The integration of these novel and classical approaches will faci litate the testing of hypotheses, developed during the course of our s tudy of the lurcher mutation, which explore the propagation of abnorma l signals and the initiation of programmed neuronal death in neurons.