ALTERED RESPONSES TO POTASSIUM IN CEREBELLAR NEURONS FROM WEAVER HETEROZYGOTE MICE

The pleiotropic weaver disease is caused by the mutation of a single a mino acid in the C-protein-linked inwardly rectifying K+ channel, GIRK 2. In homozygous (wv/wv) animals, the disease is characterized by loss of cerebellar and dopaminergic mesencephalic neurons as well as testi cular cells, which produce ataxia, fine tremors, and sterility, respec tively. Heterozygous (wv/+) animals show no obvious motor impairments, although some loss of both cerebellar and dopaminergic neurons is obs erved and wv/+ males become sterile at 3.5 months of age. Abnormal inf luxes of Na+ and Ca2+ have been linked to cerebellar cell death in wv/ wv animals, but it's not clear whether similar changes are observed in wv/+ animals. To discover whether changes in Kf-channel function or i ntracellular Ca2+ concentrations ([Ca2+](i)) play a role in the augmen ted cell loss observed in mv/+ animals when compared with +/+ animals, we studied cultured cerebellar granule cells prepared from either wv/ + or +/+ animals. Resting [Ca2+](i) was elevated in wv/+ relative to /+ animals. Further, depolarizations of cells with elevated K+ solutio ns elicited much smaller changes in [Ca2+](i) in wv/+ animals than in +/+ animals, presumably due to altered GIRK2 channel function. Both wv /+ and +/+ cells showed similar changes in [Ca2+](i) when cells were d epolarized by glutamate (1 mM), suggesting that both glutamate recepto rs and Ca2+ channels were unchanged in wv/+ animals. In summary, our r esults suggest that wv/+ cerebellar granule cells exhibit elevated res ting [Ca2+](i) levels and altered K+-channel function, which may contr ibute to the developmental abnormalities and increased cell death obse rved.