PKC activation rescues LTP from NMDA receptor blockade.
It has been proposed that a critical step in long-term potentiation (LTP) expression is the activation of presynaptic protein kinase C (PKC) after activation of postsynaptic NMDA receptors. A prediction from this "synaptic dialogue" hypothesis (Routtenberg, Trends Neurosci 1999;22:255-256) is that the well-known blockade of LTP by NMDA receptor antagonists would be rescued by direct activation of PKC. To test this prediction we recorded extracellular EPSPs in the molecular layer of the dentate gyrus (DG) in the intact, anesthetized mouse after stimulation of the perforant path. Three experimental series were performed in which tetanization was applied after continuous infusion of 1) vehicle, 2) NMDA receptor antagonist dl-2-amino-5-phosphonovaleric acid (APV) (2.5+/-1.0 nmol), or 3) both APV and then PKC activator 4-beta-phorbol-12,13-dibutyrate (PDBu, 9.0+/-1.0 pmol). LTP was reliably induced in the first series (124+/-5%, N = 6; 2.5 h after the tetanus), suppressed by APV in the second series (95+/-18%, N = 4), and restored in the third series (121+/-13%, N = 5). Decreased paired-pulse facilitation, an index of presynaptic involvement in LTP expression, was observed after tetanization in the first and third series, but not in the second series. Blockade of LTP by NMDA receptor antagonists that can be overridden by presynaptic activation of PKC is thus consistent with the proposed hypothesis. As LTP is rescued after NMDA receptor blockade in transgenic mice overexpressing growth-associated presynaptic protein GAP-43, we suppose that this protein is one of the presynaptic targets of PKC activation.
Kleschevnikov
A M
AM
Cresap Neuroscience Laboratory, Northwestern University Institute for Neuroscience, Evanston, Illinois 60208, USA.
Routtenberg
A
A
D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D008046:Lip / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D016194:Receptors, N-Methyl-D-Aspartate; D015240:Phorbol 12,13-Dibutyrate; C056639:2-amino-5-phosphopentanoic acid; D011493:Protein Kinase C; D014633:Valine