Protein synthesis required for long-term memory is induced by PKC activation on days before associative learning.
Protein synthesis has long been known to be required for associative learning to consolidate into long-term memory. Here we demonstrate that PKC isozyme activation on days before training can induce the synthesis of proteins necessary and sufficient for subsequent long-term memory consolidation. Bryostatin (Bryo), a macrolide lactone with efficacy in subnanomolar concentrations and a potential therapeutic for Alzheimer's disease, is a potent activator of PKC, some of whose isozymes undergo prolonged activation after associative learning. Under normal conditions, two training events with paired visual and vestibular stimuli cause short-term memory of the mollusc Hermissenda that lasts approximately 7 min. However, after 4-h exposures to Bryo (0.25 ng/ml) on two preceding days, the same two training events produced long-term conditioning that lasted >1 week and that was not blocked by anisomycin (1 mug/ml). Anisomycin, however, eliminated long-term memory lasting at least 1 week after nine training events. Both the nine training events alone and two Bryo exposures plus two training event regimens caused comparably increased levels of the PKC alpha-isozyme substrate calexcitin in identified type B neurons and enhanced PKC activity in the membrane fractions. Furthermore, Bryo increased overall protein synthesis in cultured mammalian neurons by up to 60% for >3 days. The specific PKC antagonist Ro-32-0432 blocked much of this Bryo-induced protein synthesis as well as the Bryo-induced enhancement of the behavioral conditioning. Thus, Bryo-induced PKC activation produces those proteins necessary and sufficient for long-term memory on days in advance of the training events themselves.
Alkon
Daniel L
DL
Blanchette Rockefeller Neurosciences Institute, 9601 Medical Center Drive, Rockville, MD 20850-3332, USA. dalkon@brni-jhu.org
Epstein
Herman
H
Kuzirian
Alan
A
Bennett
M Catherine
MC
Nelson
Thomas J
TJ
D000818:Animals; D054713:Bryostatins; D019204:GTP-Binding Proteins / Q000032:analysis; D049870:Hermissenda; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D007858:Learning; D018942:Macrolides / Q000494:pharmacology; D008568:Memory / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D011758:Pyrroles / Q000494:pharmacology
D054713:Bryostatins; D007211:Indoles; D018942:Macrolides; D011758:Pyrroles; C085989:Ro 32-0432; C046785:bryostatin 1; D011493:Protein Kinase C; D046988:Proteasome Endopeptidase Complex; D019204:GTP-Binding Proteins