Altered responses to potassium in cerebellar neurons from weaver heterozygote mice

• Published in: Experimental brain research Vol. 123; no. 3; pp. 298 - 306
• Main Authors: FOX, A. P, DLOUHY, S, GHETTI, B, HURLEY, J. H, NUCIFORA, P. G. P, NELSON, D. J, WON, L, HELLER, A
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.12.1998
• Subjects: Amino acids; Animals; Biological and medical sciences; Calcium - metabolism; Cell death; Cerebellum - cytology; Cerebellum - drug effects; Cerebellum - metabolism; Female; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Genetic aspects; Glutamate; Glutamic Acid - pharmacology; Heterozygote; Medical sciences; Mice; Mice, Neurologic Mutants; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Neurons; Neurons - drug effects; Neurons - metabolism; Potassium - pharmacology; Potassium Channels - drug effects; Potassium Channels, Inwardly Rectifying; Cerebellum; Nervous system diseases; Calcium; Granule neuron; Rodentia; Ionic channel; Ionic current; Cerebral disorder; Vertebrata; Mammalia; Cerebellar disease; Mouse; Cell death; Animal; Central nervous system disease; Ataxia; Intracellular; Mutation; Neurological disorder; Potassium
• ISSN: 0014-4819; 1432-1106
• DOI: 10.1007/s002210050572

The pleiotropic weaver disease is caused by the mutation of a single amino acid in the G-protein-linked inwardly rectifying K+ channel, GIRK2. In homozygous (wv/wv) animals, the disease is characterized by loss of cerebellar and dopaminergic mesencephalic neurons as well as testicular cells, which produce ataxia, fine tremors, and sterility, respectively. Heterozygous (wv/+) animals show no obvious motor impairments, although some loss of both cerebellar and dopaminergic neurons is observed and wv/+ males become sterile at 3.5 months of age. Abnormal influxes 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 K+-channel function or intracellular Ca2+ concentrations ([Ca2+]i) play a role in the augmented cell loss observed in wv/+ 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+ solutions 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 depolarized by glutamate (1 mM), suggesting that both glutamate receptors and Ca2+ channels were unchanged in wv/ + animals. In summary, our results suggest that wv/+ cerebellar granule cells exhibit elevated resting [Ca2+]i levels and altered K+-channel function, which may contribute to the developmental abnormalities and increased cell death observed.