Gangliosides (sialic acid-containing glycosphingolipids) play important roles in many physiological functions, including synaptic plasticity in the hippocampus, which is considered as a cellular mechanism of learning and memory. In the present study, three types of synaptic plasticity, long-term potentiation (LTP), long-term depression (LTD) and reversal of LTP (depotentiation, DP), in the field excitatory post-synaptic potential in CA1 hippocampal neurons and learning behavior were examined in β1,4-N-acetylgalactosaminyltransferase (β1,4 GalNAc-T; GM2/GD2 synthase) gene transgenic (TG) mice, which showed a marked decrease in b-pathway gangliosides (GQ1b, GT1b and GD1b) in the brain and isolated hippocampus compared with wild-type (WT) mice. The magnitude of the LTP induced by tetanus (100 pulses at 100 Hz) in TG mice was significantly smaller than that in control WT mice, whereas there was no difference in the magnitude of the LTD induced by three short trains of low-frequency stimulation (LFS) (200 pulses at 1 Hz) at 20 min intervals between the two groups of mice. The reduction in the LTP produced by delivering three trains of LFS (200 pulses at 1 Hz, 20 min intervals) was significantly greater in the TG mice than in the WT mice. Learning was impaired in the four-pellet taking test (4PTT) in TG mice, with no significant difference in daily activity or activity during the 4PTT between TG and WT mice. These results suggest that the overexpression of β1,4 GalNAc-T resulted in altered synaptic plasticity of LTP and DP in hippocampal CA1 neurons and learning in the 4PTT, and this is attributable to the shift from b-pathway gangliosides to a-pathway gangliosides.

Gangliosides (sialic acid-containing glycosphingolipids) play important roles in many physiological functions, including synaptic plasticity in the hippocampus, which has been suggested as the basal cellular process of learning and memory in the brain. In the present study, long-term potentiation (LTP) and long-term depression (LTD) in CA1 hippocampal neurons and learning behavior were examined in mice treated with d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (d-PDMP), an inhibitor of ganglioside biosynthesis. Mice treated with d-PDMP, but not those treated with l-PDMP, showed impairment of LTP induction in hippocampal CA1 neurons without any significant change in LTD formation and also showed a failure of learning in the 4-pellet taking test. These results indicate that de novo synthesis of gangliosides in the brain is involved in synaptic plasticity of LTP in mouse hippocampal CA1 neurons and plays important roles in learning and memory.In rodent CA1 hippocampal neurons, long-term potentiation (LTP) and long-term depression (LTD) are two types of synaptic plasticity, considered to be the cellular basis of learning and memory in the brain (6,21). LTP is a state of persistent synaptic enhancement induced by a brief period of high frequency electrical stimulation (HFS) of afferents (4, 5), while LTD is another activity-dependent synaptic phenomenon in which low-frequency afferent stimulation (LFS) depresses a synaptic response in a naive pathway (8,19). Gangliosides (sialic acid-containing glycosphingolipids) are abundant in the plasma membrane, especially in the termini and synapses of neural tissue (1). Ganglioside biosynthesis occurs by sequential glycosylation reactions via two major pathways designated the "a-pathway" (GM2, GM1a, and GD1a) and "b-pathway" (GD3, GD2, GD1b, GT1b, and GQ1b), with a common precursor, GM3. The analogous steps in the two pathways are catalyzed by the same glycosyltransferases (13,17). We previously studied the effects of GM1 and GQ1b on induction of LTP in CA1 neurons in rat hippocampal slices and showed that LTP is enhanced by bath application of either ganglioside, with GQ1b having a significantly greater effect than GM1 (12). In our recent study (14), we investigated LTP and LTD in the field excitatory post-synaptic potential (EPSP) in CA1 hippocampal neurons and learning behavior in β1,4-N-acetylgalactosaminyltransferase (β1,4 GalNAc-T; GM2/GD2 synthase) gene transgenic (TG) mice (10), which showed a significant decrease in levels of b-pathway gangliosides (GQ1b, GT1b, and GD1b) and a significant increase in lev-