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Neural Plasticity
Volume 2014, Article ID 196812, 11 pages
http://dx.doi.org/10.1155/2014/196812
Research Article

Blockade of Lysosomal Acid Ceramidase Induces GluN2B-Dependent Tau Phosphorylation in Rat Hippocampal Slices

Département de biologie médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada G9A 5H7

Received 15 April 2014; Revised 24 July 2014; Accepted 8 August 2014; Published 8 September 2014

Academic Editor: Zygmunt Galdzicki

Copyright © 2014 Marie-Elaine Laurier-Laurin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The lysosomal acid ceramidase, an enzyme known to limit intracellular ceramide accumulation, has been reported to be defective in neurodegenerative disorders. We show here that rat hippocampal slices, preincubated with the acid ceramidase inhibitor (ACI) d-NMAPPD, exhibit increased N-methyl-D-aspartate (NMDA) receptor-mediated field excitatory postsynaptic potentials (fEPSPs) in CA1 synapses. The ACI by itself did not interfere with either paired pulse facilitation or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-mediated fEPSPs, indicating that its influence on synaptic transmission is postsynaptic in origin and specific to the NMDA subtype of glutamate receptors. From a biochemical perspective, we observed that Tau phosphorylation at the Ser262 epitope was highly increased in hippocampal slices preincubated with the ACI, an effect totally prevented by the global NMDA receptor antagonist D/L(−)-2-amino-5-phosphonovaleric acid (AP-5), the calcium chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA), and the GluN2B (but not the GluN2A) receptor antagonist RO25-6981. On the other hand, preincubation of hippocampal slices with the compound KN-62, an inhibitor known to interfere with calcium/calmodulin-dependent protein kinase II (CaMKII), totally abolished the effect of ACI on Tau phosphorylation at Ser262 epitopes. Collectively, these results provide experimental evidence that ceramides play an important role in regulating Tau phosphorylation in the hippocampus via a mechanism dependent on GluN2B receptor subunits and CaMKII activation.