Adenylyl cyclase-dependent form of chemical long-term potentiation triggers translational regulation at the elongation step

• Published in: Neuroscience Vol. 116; no. 3; pp. 743 - 752
• Main Authors: Chotiner, J.K, Khorasani, H, Nairn, A.C, O’Dell, T.J, Watson, J.B
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.01.2003; Elsevier
• Subjects: Adenylyl Cyclases - physiology; Animals; Biological and medical sciences; Central nervous system; chemical induction; Electrophysiology; eukaryotic elongation factor 2; Fundamental and applied biological sciences. Psychology; Hippocampus - enzymology; In Vitro Techniques; Long-Term Potentiation - physiology; LTP; Male; Mice; Mice, Inbred C57BL; mRNA/protein synthesis; phosphorylation; Protein Biosynthesis - physiology; Synaptic Transmission - physiology; translational regulation; Vertebrates: nervous system and sense organs; CPM; eEF2; DMSO; fEPSPs; APV; mRNA/protein synthesis; LTP; IEGs; mRNA; cAMP; ActD; ANOVA; NMDA; chemLTP; phosphorylation; BLOTTO; FSK; PBS; AC; eIF4E; eukaryotic elongation factor 2; chemical induction; PKA; PP2A; ACSF; Arc; CaMKII; CXM; translational regulation; ANI; Potentiation; Central nervous system; Electrophysiology; Phosphorus-oxygen lyases; Lyases; Adenylate cyclase; Regulation(control); Messenger RNA; Synaptic transmission; Translation; Enzyme; Rodentia; Long term; Vertebrata; Mammalia; Mouse; Protein synthesis; Excitatory postsynaptic potential; Hippocampus; Brain (vertebrata)
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/S0306-4522(02)00797-2

The persistent maintenance of long-term potentiation requires both messenger RNA and protein synthesis. While there is mounting evidence for an active role of protein synthesis in hippocampal long-term potentiation, the nature of mechanisms underlying its regulation has not yet been established. We used a previously described chemical long-term potentiation protocol [J Neurosci 19 (1999) 2500] to address the hypothesis that signaling mechanisms, involved in long-lasting long-term potentiation, directly regulate protein synthesis. Chemical long-term potentiation is an N-methyl- d-aspartate receptor-dependent form of plasticity, which relies on both synaptic activity, in the form of spontaneous bursting induced by high concentrations of K + and Ca 2+, and cyclic AMP/adenylyl cyclase signaling. We found that chemical long-term potentiation in CA1 of the mouse hippocampus lasts for at least 3 hours and requires both messenger RNA and protein synthesis. However, surprisingly de novo total protein synthesis was paradoxically decreased at 1 hour after long-term potentiation induction. Consistent with the decrease in total protein synthesis in potentiated CA1, phosphorylation of eukaryotic elongation factor 2 was increased and is likely responsible for inhibition of translation at the elongation step. Increased phosphorylation of eukaryotic elongation factor 2 was dependent on coincident cyclic AMP/adenylyl cyclase activation and synaptic activity and required N-methyl- d-aspartate receptor activation. Despite the inhibition in total protein synthesis, the level of the immediate early gene protein Arc (activity regulated cytoskeleton-associated protein) increased at 1 hour after chemical long-term potentiation induction. Taken together, the results suggest that regulation at the elongation step of protein synthesis contributes to persistent forms of long-term potentiation.