Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 45, Pages 16432-16437Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0508001102
Keywords
bryostatin; PKC isozymes
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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 approximate to 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 mu g/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 a-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-incluced protein synthesis as well as the Bryo-induced enhancement of the behavioral conditioning. Thus, Bryo-incluced PKC activation produces those proteins necessary and sufficient for long-term memory on days in advance of the training events themselves.
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