Ceramide-induced sustained depression of synaptic currents mediated by ionotropic glutamate receptors in the hippocampus: an essential role of postsynaptic protein phosphatases.
Ceramide, a sphingomyelin-derived second messenger, mediates cellular signals of cytokines such as tumor necrosis factor-alpha that are rapidly produced in the brain in response to vigorous neuronal activity and tissue injury. Using whole-cell patch-clamp recordings, the present study examined whether ceramide modulated excitatory postsynaptic currents mediated by ionotropic glutamate receptors in CA1 pyramidal neurons of rat hippocampal slices. Application of N-acetyl-D-sphingosine, a synthetic cell-permeable ceramide analog, promptly produced a slight increase of excitatory postsynaptic current amplitude lasting for about 3 min. However, this transient enhancement was followed by a profoundly delayed-onset, sustained depression of synaptic excitatory postsynaptic currents in a concentration-dependent fashion (1-30 microM). This ceramide-induced sustained depression was not associated with changes in paired-pulse facilitation, a phenomenon resulting from an alteration of presynaptic transmitter release. Dihydro-N-acetyl-D-erythro-sphingosine (10 microM), an inactive analog of N-acetyl-D-sphingosine, did not affect synaptic excitatory postsynaptic currents, indicating the specificity of N-acetyl-D-sphingosine's action. The induction of ceramide-induced sustained depression was primarily dependent on the activation of postsynaptic protein phosphatases, being considerably blocked by loading 30 nM okadaic acid (a potent inhibitor of protein phosphatases 1 and 2A) into neurons. In addition, following a stable establishment of ceramide-induced sustained depression, a protocol for inducing long-term depression caused no additional decreases in excitatory postsynaptic current amplitude, and vice versa. The study suggests that ceramide induces a long-term depressed modulation on synaptic transmission mediated by ionotropic glutamate receptors in the hippocampus, possibly through the activation of postsynaptic protein phosphatases 1 and 2A. In addition, ceramide-induced sustained depression seems to share some common mechanisms with long-term depression, such as the cascades of events resulting from the activation of protein phosphatases. Collectively, the long-term depressed modulation of ceramide on ionotropic glutamate receptor-mediated functions may be particularly important in various physiological and/or pathological conditions, in which the ceramide signaling pathway is activated in the mammalian brain.
Yang
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Department of Physiology and Biophysics, P.O. Box 90048-503, National Defense Medical Center, Taipei 114, Taiwan, China. snyang@ndmctsgh.edu.tw
D000818:Animals; D002518:Ceramides / Q000378:metabolism* / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D018408:Patch-Clamp Techniques; D010749:Phosphoprotein Phosphatases / Q000187:drug effects* / Q000378:metabolism*; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology*
D002518:Ceramides; D017470:Receptors, Glutamate; D010749:Phosphoprotein Phosphatases