Protein synthesis required
for long-term memory is induced by PKC activation on days before associative
Daniel L. Alkon, Herman Epstein, Alan Kuzirian, M.
Catherine Bennett, and Thomas J. Nelson
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 ~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 (1µg/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 ?-isozome 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.
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