The weaver mouse: a most cantankerous rodent.

Abstract

protein evoked any aspect of the mutant phenotype in a weaver cell remained unknown. The question has now been solidly answered in the affirmative. Culturing granule cells from wild-type, wv/wv, and wv! + cerebella, Surmeier et al. (19) have shown in this issue of the Proceedings that the Girk2wv mutation significantly alters their G-protein-activated potassium currents. The properties of the currents in wild-type cells suggest that the normal granule cell makes a tetrameric channel that contains both GIRK1 and GIRK2 subunits, with little evidence for the presence of homomeric GIRK1 channels. The mutant protein thus acts as a semidominant monkey wrench in the normally smooth operation of the ionic homeostasis of the granule cell. The authors discuss the possible role of glutamate in linking the channel defect to the granule cell death phenotype. They hypothesize that if glutamate were normally present in the environment of the early postmitotic granule cell, then metabotropic glutamate receptors could be activated leading to an in-rush of calcium with an associated triggering of the GIRK channel(s) to achieve repolarization. The wv/wv granule cell would be at a disadvantage in this situation, however, and the resulting sustained depolarization might lead to excessive calcium entry and death. This is an intriguing hypothesis given the findings of Trenkner (20) that the weaver granule cell defect is rescued by NMDA blockers as well as those of Komuro and Rakic (21) that the rates of granule cell migration from the external to internal granule cell layer are modulated by NMDA-type glutamate channels. As might be anticipated from its history, however, the clouds