Cerebellar neurons lacking complex gangliosides degenerate in the presenceof depolarizing levels of potassium

Mice engineered to lack GM2/GD2 synthase (GalNAc-T), with resultant deficit of GM2, GD2, and all gangliotetraose gangliosides, were originally describ ed as showing a relatively normal phenotype with only a slight reduction in nerve conduction. However, a subsequent study showed that similar animals suffer axonal degeneration, myelination defects, and impaired motor coordin ation. We have examined the behavior of cerebellar granule neurons from the se neonatal knockouts in culture and have found evidence of impaired capaci ty for Ca2+ regulation. These cells showed relatively normal behavior when grown in the presence of physiological or moderately elevated K+ but gradua lly degenerated in the presence of high K+. This degeneration in depolarizi ng medium was accompanied by progressive elevation of intracellular calcium and onset of apoptosis, phenomena not observed with normal cells. No diffe rences were detected in cells from normal vs. heterozygous mice. These find ings suggest that neurons from GalNAc-T knockout mice are lacking a calcium regulatory mechanism that is modulated by one or more of the deleted gangl iosides, and they support the hypothesis that maintenance of calcium homeos tasis is one function of complex gangliosides during, and perhaps subsequen t to, neuronal development.