Mice expressing only monosialoganglioside GM3 exhibit lethal audiogenic seizures

Gangliosides are a family of glycosphingolipids that contain sialic acid. A lthough they are abundant on neuronal cell membranes, their precise functio ns and importance in the central nervous system (CNS) remain largely undefi ned. We have disrupted the gene encoding GD3 synthase (GD3S), a sialyltrans ferase expressed in the CNS that is responsible for the synthesis of b-seri es gangliosides. GD3S-/- mice, even with an absence of b-series ganglioside s, appear to undergo normal development and have a normal life span. To fur ther restrict the expression of gangliosides, the GD3S mutant mice were cro ssbred with mice carrying a disrupted GalNAcT gene encoding beta1,4-N-acety lgalactosaminyltransferase. These double mutant mice expressed GM3 as their major ganglioside. In contrast to the single mutant mice, the double mutan ts displayed a sudden death phenotype and were extremely susceptible to ind uction of lethal seizures by sound stimulus. These results demonstrate uneq uivocally that gangliosides play an essential role in the proper functionin g of the CNS.