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-α 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 μM). 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 μM), 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.