John Lisman, PhD
Zalman Abraham Kekst Professor of Neuroscience Department of Biology
Brandeis University
(October 12, 2017)
The Critical Role of CaMKII in Memory Storage: 6 Key Physiological and Behavioral Tests
Our memories are part of what defines us as individuals and thinking beings. How memory can be encoded in the wet-ware of the brain is a question that has occupied many scientists and philosophers. As our understanding of biology at the cellular and molecular level has progressed, the question of how memories are stored has taken on a more biochemical flavor. Beginning in the 1980s, work on CaMKII suggested that it might be a biochemical switch capable of holding memory.
In 1984 Francis Crick published an opinion piece laying out how the brain might get around the problem of molecular turnover (which occurs on a scale of days to weeks) for building a stable memory switch. The model he favored was one of a multimeric synaptic protein in which “memory” could be stored in a modification. The modified form of the protein could be maintained in the face of protein turnover by specifying that turnover occurred at the subunit level and that new subunits being incorporated into a holoenzyme could take on the memory state of the parent multimer. The next year, 1985, John Lisman published a model in PNAS showing that an autophosphorylating kinase/phosphatase pair could store memory indefinitely.
These two models gave a pretty decent description of CaMKII, an enzyme that was first discovered in the late ‘70s in Paul Greengard’s lab by Howard Schulman. The deep biochemical work on CaMKII from Mary Kennedy and a host of others showed that CaMKII is multimeric, autophosphorylating protein kinase that is localized to synaptic domains. Over the next two decades it was shown by the Lisman lab and others that its autophosphorylated state is associated with synaptic potentiation and memory. The one thing that was lacking was a demonstration that there could be subunit exchange and that has now been shown by Meg Stratton’s in vitro work. The Lisman lab’s most recent paper showing that a memory could be erased by flooding the synapse with a dead kinase argued that exchange is probably happening in vivo too and that it is critical to maintaining long-term memories.