Impairment of hippocampal long-term potentiation and failure of learning in mice treated with d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol

Abstract

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-

Preferential Regulation of Γ‐Secretase‐Mediated Cleavage of APP by Ganglioside GM1 Reveals a Potential Therapeutic Target for Alzheimer's Disease

“…According to the mouse body weight, one intraperitoneal injection of 30 mg kg −1 D‐PDMP (P7340, Sigma‐Aldrich, Tokyo, Japan), D‐PDMP powder was dissolved in saline containing 5% Tween 80. [ 43 ] And the mice were divided into three subgroups: WT CTRL, APP/PS1 CTRL, and APP/PS1 D‐PDMP.…”

The Role of Gangliosides in Neurodevelopment

“…In particular, GQ1b was shown to participate in activity-dependent LTP in CA1 neurons of guinea pig hippocampal slices, through modulation of NMDA receptors/Ca 2+ channels [ 88 ], while transgenic mice with decreased levels of GQ1b exhibited learning impairment and an altered synaptic plasticity, as evidenced by an attenuation of the induction of LTP in hippocampal CA1 neurons [ 89 ]. In mice, inhibition of the biosynthesis of b-pathway gangliosides, including GQ1b, also resulted in impairment of LTP induction in hippocampal CA1 neurons, accompanied by failure to learn in a simple memory task [ 90 ]. Moreover, intraperitoneal administration of ganglioside was able to reverse the lead-induced impairment of LTP activity in rat brain [ 91 ].…”

The role of sphingolipids in neuronal plasticity of the brain

“…Treatment of cells with exogenous gangliosides, particularly monosialoganglioside GM1, promotes the synaptic plasticity mechanisms responsible for LTP in hippocampal neurons (Okada et al 1994;Fujii et al 2002), thereby ameliorating various types of CNS injuries. Pharmacologic or genetic impairment of complex ganglioside synthesis has negative effects on hippocampal LTP, and reduces learning ability and other cognitive functions in mice (Ikarashi et al 2011;Fujiwara et al 2012;Sha et al 2014). The molecular mechanisms that underlie LTP are multiple and heterogeneous, and different forms of LTP occur in different brain areas and neuronal circuits.…”