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The Journal of Neuroscience, May 15, 1998, 18(10):3537-3547
The weaver Mutation Causes a Loss of Inward Rectifier Current Regulation in Premigratory Granule Cells of the Mouse Cerebellum
Paola Rossi, Giovanna De Filippi, Simona Armano, Vanni Taglietti, and Egidio D'Angelo Istituto di Fisiologia Generale, I-27100, Pavia, Italy, and Istituto Nazionale per la Fisica della Materia, Pavia Unit, Italy
Considerable interest has recently focused on the weaver mutation, which causes inward rectifier channel alterations leading to profound impairment of neuronal differentiation and to severe motor dysfunction in mice (). The principal targets of mutation are cerebellar granule cells, most of which fail to differentiate and degenerate in a premigratory position (,). Two hypotheses have been put forward to explain the pathogenetic role of mutant inward rectifier channels: namely that inward rectifier channel activity is either lacking () or altered (; ; ). We have examined this question by recording inward rectifier currents from cerebellar granule cells in situ at different developmental stages in wild-type and weaver mutant mice. In wild-type mice, the inward rectifier current changed from a G-protein-dependent activation to a constitutive activation as granule cells developed from premigratory to postmigratory stages. In weaver mutant mice, G-protein-dependent inward rectifier currents were absent in premigratory granule cells. A population of putative granule cells in the postmigratory position expressed a constitutive inward rectifier current with properties compatible with mutated GIRK2 channels expressed in heterologous systems. Because granule cells degenerate at the premigratory stage (), the loss of inward rectifier current and its regulation of membrane potential are likely to play a key role in the pathogenesis of weaver neuronal degeneration.
Key words: cerebellum; granule cell; channellopathy; weaver; inward rectifier; mouse
Copyright © 1998 Society for Neuroscience 0270-6474/98/18103537-11$05.00/0
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