Description:

Protein synthesis has long been known to be required for associative learning to consolidate into long-term memory. In our recent work at the MBL, we were able to demonstrate that PKC isozyme activation on days before training can induce the synthesis of proteins necessary and sufficient for subsequent long-term memory (LTM) consolidation. We believe that this work, coupled with correlative electrophysiology that is consistent with the biochemistry, is a major step forward in our understanding of how long-term memory is stored in brains. Considering that the key drug used for our current experiments, bryostatin, is about to go into clinical trials, these findings once more illustrate the power of marine models for uncovering fundamental principles of brain function - particularly as they relate to man. We have used the resources of the BRC to pursue the underlying electrophysiological mechanisms.

Progress:

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 in the mollusc Hermissenda that lasts about 7 min. However, after four-hour exposures to Bryo (0.25ng/ml), on two preceding days, the same 2 training events produced long-term conditioning that lasted more than 1 week and that was not blocked by anisomycin (1µg/ml). Anisomycin, however, eliminated LTM lasting at least one week after 9 training events. Both the 9 training events and Bryo (x2)+2 training event regimens caused comparably increased levels of the PKC -isozyme substrate calexcitin in identified Type B neurons and enhanced PKC activity in both cytosol and membrane fractions. Furthermore, Bryo increased overall protein synthesis in cultured mammalian neurons by up to 60% for more than 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 required for long-term memory on days in advance of the training events themselves.