Lurcher (Lc) is a spontaneous, semidominant mouse neurological mutation(1). Heterozygous Lurcher mite (Lc/+) display ataxia as a result of a selective, coil-autonomous and apoptotic death of cerebellar Purkinje cells during postnatal develoment(2-4). Homozygous Lurcher mice (Lc/Lc) die shortly after birth because of a massive loss of mid-and hindbrain neurons during late embryogenesis(5). We have used positional cloning to identify the mutations responsible for neurodegeneration in two independent Lc alleles as G-to-A transitions that change a highly conserved alanine to a threonine residue in transmembrane domain III of the mouse delta 2 glutamate receptor gene (GluR delta 2). Lc/+ Purkinje cells have a very high membrane conductance and a depolarized resting potential, indicating the presence of a large, constitutive inward current. Expression of the mutant GluR delta 2(Lc) protein in Xenopus oocytes confirmed these results, demonstrating that Lc is inherited as a neurodegenerative disorder resulting from a gain-of-function mutation in a glutamate receptor gene. Thus the activation of apoptotic neuronal death in Lurcher mice may provide a physiologically relevant model for excitotoxic cell death.