Tumor necrosis factor-alpha-induced neutral sphingomyelinase-2 modulates synaptic plasticity by controlling the membrane insertion of NMDA receptors.
The insertion and removal of NMDA receptors from the synapse are critical events that modulate synaptic plasticity. While a great deal of progress has been made on understanding the mechanisms that modulate trafficking of NMDA receptors, we do not currently understand the molecular events required for the fusion of receptor containing vesicles with the plasma membrane. Here, we show that sphingomyelin phosphodiesterase 3 (also known as neutral sphingomyelinase-2) is critical for tumor necrosis factor (TNF) alpha-induced trafficking of NMDA receptors and synaptic plasticity. TNFalpha initiated a rapid increase in ceramide that was associated with increased surface localization of NMDA receptor NR1 subunits and a specific clustering of NR1 phosphorylated on serines 896 and 897 into lipid rafts. Brief applications of TNFalpha increased the rate and amplitude of NMDA-evoked calcium bursts and enhanced excitatory post-synaptic currents. Pharmacological inhibition or genetic mutation of neutral sphingomyelinase-2 prevented TNFalpha-induced generation of ceramide, phosphorylation of NR1 subunits, clustering of NR1, enhancement of NMDA-evoked calcium flux and excitatory post-synaptic currents.
Wheeler
David
D
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Knapp
Edward
E
Bandaru
Veera V R
VV
Wang
Yue
Y
Knorr
David
D
Poirier
Christophe
C
Mattson
Mark P
MP
Geiger
Jonathan D
JD
Haughey
Norman J
NJ
D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods; D016537:Gangliosidosis, GM1 / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000814:Aniline Compounds; D001597:Benzylidene Compounds; D002518:Ceramides; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; C468773:GW 4869; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D014409:Tumor Necrosis Factor-alpha; D012694:Serine; C107180:Smpd3 protein, rat; D013108:Sphingomyelin Phosphodiesterase; D002118:Calcium; C001996:thermozymocidin