In the neurological mutant mouse weaver, granule cell precursors proliferate normally in the external germinal layer of the cerebellar cortex, but fail to differentiate. Granule neurons purified from weaver cerebella have greatly reduced G protein-activated inwardly rectifying K+ currents; instead, they display a constitutive Na+ conductance. Expression of the weaver GIRK2 channel in oocytes confirms that the mutation leads to constitutive activation, loss of monovalent cation selectivity, and increased sensitivity to three channel blockers. Pharmacological blockade of the Na+ influx in weaver granule cells restores their ability to differentiate normally. Thus, Na+ flux through the weaver GIRK2 channel underlies the failure of granule cell development in situ.
Bibliographical noteFunding Information:
The authors wish to thank Sheri McKinney for preparing the mixed cerebellar cultures, Peter Hoff for the assistance in setting up the electrophysiological equipment, and Dillon Patterson for assistance in nonradioactive in situ analysis. This work was supported by National Institutes of Health grants NS-34469 (M. E. H.), MH-49176 (H. A. L.), and GM-29836 (H. A. L.), March of Dimes Birth Defect Foundation grant 1-FY95-0782 (M. E. H.), and by postdoctoral fellowships from the American Heart Association (P. K.), the Human Frontiers Science Program Organization (K. J. M.), and the National Institutes of Health (J. H. M.).