title: Neuromuscular synaptic transmission in aged ganglioside-deficient mice.
abstract: Gangliosides are sialylated glycosphingolipids that are present in high density on neuronal membranes, especially at synapses, where they are assumed to play functional or modulating roles. Mice lacking GM2/GD2-synthase express only the simple gangliosides GD3 and GM3 and develop progressive motor behaviour deficits upon ageing, apparently due to failing complex ganglioside-dependent maintenance and/or repair processes or, alternatively, toxic GM3/GD3 accumulation. We investigated the function of neuromuscular junctions (NMJs) of aged (>9 month-old) GM2/GD2-synthase null-mutant mice, because synaptic dysfunction might develop with age and could potentially contribute to the late-onset motor phenotype. In addition, we studied NMJs of old mice lacking GD3-synthase (expressing only O- and a-series gangliosides), which do not show an overt neurological phenotype but may develop subclinical synaptic deficits. Detailed electrophysiological analyses showed subtle changes in presynaptic neurotransmitter release. Acetylcholine release at 40 Hz nerve stimulation at aged GM2/GD2-synthase null-mutant NMJs ran down slightly more pronounced than at wild-type NMJs, and spontaneous acetylcholine release rate at GD3-synthase null-mutant NMJs was somewhat higher than at wild-type, selectively at 25 °C bath temperature. Interestingly, we observed faster kinetics of postsynaptic electrophysiological responses at aged GD3-synthase null-mutant NMJs, not previously seen by us at NMJs of young GD3-synthase null-mutants or other types of (aged or young) ganglioside-deficient mice. These kinetic changes might reflect a change in postsynaptic acetylcholine receptor behaviour. Our data indicate that it is highly unlikely that transmission failure at NMJs contributes to the progressive motor defects of aged GM2/GD2-synthase null-mutants and that, despite some kinetic changes of synaptic signals, neuromuscular transmission remains successful in aged GD3-synthase null-mutant mice. Apparently, mutual redundancy of the different gangliosides in supporting presynaptic function, as observed previously by us in young mice, remains adequate upon ageing or, alternatively, gangliosides have only relatively little direct impact on neuromuscular synaptic function, even in aged mice.
authors.affiliation: Department of Neurology, Leiden University Medical Centre, PO Box 9600, NL-2300 RC Leiden, The Netherlands.
authors.forename: Femke M P
authors.initials: FM
authors.lastname: Zitman
authors.forename: Boyan
authors.initials: B
authors.lastname: Todorov
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Verschuuren
authors.forename: Bart C
authors.initials: BC
authors.lastname: Jacobs
authors.forename: Keiko
authors.initials: K
authors.lastname: Furukawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Furukawa
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: Willison
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Plomp
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000375:Aging / Q000235:genetics / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism; D005260:Female; D018737:Hand Strength / Q000502:physiology; D006982:Hypertonic Solutions / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D017350:N-Acetylgalactosaminyltransferases / Q000172:deficiency*; D009469:Neuromuscular Junction / Q000235:genetics*; D011188:Potassium / Q000494:pharmacology; D012799:Sialyltransferases / Q000172:deficiency*; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics*; D013696:Temperature
chemical_list: D006982:Hypertonic Solutions; D017350:N-Acetylgalactosaminyltransferases; C023220:(N-acetylneuraminyl)-galactosylglucosylceramide N-acetylgalactosaminyltransferase; D012799:Sialyltransferases; C043662:alpha-N-acetylneuraminate alpha-2,8-sialyltransferase; D000109:Acetylcholine; D011188:Potassium; D002118:Calcium