The aim of the project is to study the role of the enzyme CaM Kinase II in the modification of synapses, which are the sites of communication between nerve cells. It is known that previous activity can modify a synapse so that the communication is either strengthened (potentiated) or weakened (depressed). Studies on a model system with slices from the hippocampus, a brain region involved in the formation of memory, indicate that the frequency of synaptic activity determines whether potentiation or depression will occur. Furthermore, these studies show that both long-term potentiation (LTP) and long-term depression (LTD) require an increase in the intracellular levels of calcium ion (Ca2+), an event, which leads to the activation of CaM kinase II. A central hypothesis of the present project is that CaM kinase II is the sensor that transduces frequency information into a specific synaptic modification. CaM kinase II modifies itself by a process called autophosphorylation, which can occur, at several different sites on the molecule. It is proposed that CaM kinase II can detect the temporal pattern of Ca2+ waves through autophosphorylation on two of these sites, one, which occurs only in the presence and the other only in the absence of Ca2+. Studies using isolated synaptic structures that contain CaM kinase II will be conducted to verify the above proposal. Parallel studies will investigate changes in the phosphorylation state of CaM Kinase II in slices of hippocampus following high- and low-frequency stimulation to produce LTP and LTD respectively. The changes that are secondary to the self-modification of CaM kinase II will also be identified.
The long-term goal of these studies is to uncover how memories are acquired in the brain. It is generally accepted that this process depends on lasting modification of the communication between nerve cells, or, more precisely, on activity-dependent changes in the efficiency of synapses. During this process, the temporal pattern or frequency of activity is likely to represent one dimension of the information, which needs to be detected and transduced. The present proposal, if validated, would provide a molecular mechanism for frequency detection at the synapse and clarify initial stages in the cascade of events that leads to lasting changes in synaptic efficiency.
