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J Biol Chem, Vol. 274, Issue 35, 25173-25180, August 27, 1999

Neuronal Sensitivity to Tetanus Toxin Requires Gangliosides

Lura C. Williamson, Karen E. Bateman, Julianne C. M. Clifford^§, and Elaine A. Neale

From the  Laboratory of Developmental Neurobiology, NICHHD, National Institutes of Health, Bethesda, Maryland 20892-4480 and the ^§ Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892

Tetanus toxin produces spastic paralysis in situ by blocking inhibitory neurotransmitter release in the spinal cord. Although di- and trisialogangliosides bind tetanus toxin, their role as productive toxin receptors remains unclear. We examined toxin binding and action in spinal cord cell cultures grown in the presence of fumonisin B₁, an inhibitor of ganglioside synthesis. Mouse spinal cord neurons grown for 3 weeks in culture in 20 µM fumonisin B₁ develop dendrites, axons, and synaptic terminals similar to untreated neurons, even though thin layer chromatography shows a greater than 90% inhibition of ganglioside synthesis. Absence of tetanus and cholera toxin binding by toxin-horseradish peroxidase conjugates or immunofluorescence further indicates loss of mono- and polysialogangliosides. In contrast to control cultures, tetanus toxin added to fumonisin B₁-treated cultures does not block potassium-stimulated glycine release, inhibit activity-dependent uptake of FM1-43, or abolish immunoreactivity for vesicle-associated membrane protein, the toxin substrate. Supplementing fumonisin B₁-treated cultures with mixed brain gangliosides completely restores the ability of tetanus toxin to bind to the neuronal surface and to block neurotransmitter release. These data demonstrate that fumonisin B₁ protects against toxin-induced synaptic blockade and that gangliosides are a necessary component of the receptor mechanism for tetanus toxin.

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