…e la bonne vienne y mettre son grain de sel – erasing memory to study it
In Eugene Ionesco’s play “The Chairs”, written originally in French, an old woman reassures her husband that she does not remember his often repeated story . . that she actually takes salt to help her forget . . .
Calcium/calmodulin-dependent protein kinase (CaMK) is a major mediator of signaling in a wide range of cellular functions, including ion channel and cell cycle regulation and neurotransmitter synthesis and release. For years, scientists have studied the molecular basis of memory storage, trying to find the molecules that store memory, just as DNA stores genetic memory. In a study published this week in the Journal of Neuroscience, Brandeis University researchers report for the first time that memory storage can be induced and then biochemically erased in slices of rat hippocampus by manipulating a protein kinase known as CaMKII.
“The core problem in memory research has been understanding what the storage molecule actually is. Identifying this molecule is essential to understanding memory itself as well as any disease of memory, ” explained lead author John Lisman. “With this study, we have confirmed CaMKII as a memory molecule.”
The research involved electrically stimulating neuronal synapses to strengthen them, a process known as long-term potentiation (LTP). This process has served as a model system for studying memory. CaMKII has been a leading candidate as a memory molecule because it is persistently activated after LTP induction and can enhance synaptic transmission, properties that are necessary for a memory molecule.
Like a computer whose electronics change with the addition of new information, molecular activity in the hippocampus, where memory is stored in the brain, changes as memory is being stored. In this study, Lisman and his colleagues showed that they could saturate the memory stores. However, when CaMKII was chemically attacked and previous memory erased, it then became possible to insert new memories in the synapses.
Alzheimer’s and other diseases in which memory loss plays a major role will benefit from this new understanding. Of particular importance may be conditions like epilepsy, which involves synapses that have become overly strengthened. The new research shows how synapses can be weakened by attacking memory molecules.
Lisman’s lab plans further research to better understand what happens to the CaMKII after it is attacked. By using fluorescent forms of CaMKII, it will be possible to determine whether the kinase leaves the synapse after inhibitor is applied. This provides a way to directly visualize the forgetting process and complements previous work done in Lisman’s laboratory showing that when LTP is induced (as during learning), CaMKII moves into the synapse.
The Journal of Neuroscience, May 9, 2007, 27(19):5190-5199; doi:10.1523/JNEUROSCI.5049-06.2007.
Reversal of Synaptic Memory by Ca2+/Calmodulin-Dependent Protein Kinase II Inhibitor
Magdalena Sanhueza,1 * Charmian C. McIntyre,2 * and John E. Lisman2
1Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago 780-0024, Chile, and 2Biology Department and Volen Center for Complex Systems–MS 008, Brandeis University, Waltham, Massachusetts 02454
Correspondence should be addressed to John E. Lisman, Biology Department and Volen Center for Complex Systems–MS 008, Brandeis University, 415 South Street, Waltham, MA 02454. Email: Lisman@brandeis.edu
Long-term potentiation (LTP) is an activity-dependent strengthening of synapses that is thought to underlie memory storage. Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been a leading candidate as a memory molecule because it is persistently activated after LTP induction and can enhance transmission. Furthermore, a mutation that blocks persistent activation blocks LTP and forms of learning. However, direct evidence for a role of the kinase in maintaining synaptic strength has been lacking. Here, we show that a newly developed noncompetitive inhibitor of CaMKII strongly reduces synaptic transmission in the CA1 region of the hippocampal slice. This occurs through both presynaptic and postsynaptic action. To study the role of CaMKII in the maintenance of LTP, inhibitor was applied after LTP induction and then removed. Inhibition occurred in both LTP and control pathways but only partially recovered. The nonrecovering component was attributable primarily to a postsynaptic change. To test whether nonrecovery was attributable to a persistent reversal of LTP, we first saturated LTP and then transiently applied inhibitor. This procedure allowed additional LTP to be induced, indicating a reversal of an LTP maintenance mechanism. This is the first procedure that can reverse LTP by chemical means and suggests that a component of synaptic memory is attributable to CaMKII. The procedure also enhanced the LTP that could be induced in the control pathway, consistent with the idea that CaMKII is involved in controlling basal synaptic strength, perhaps as a result of LTP that occurred in vivo.
Key words: CaMKII; depotentiation; hippocampus; LTP; maintenance; memory