Memory function is thought to involve changes in the strength of synaptic connections between neurons that are activated in the appropriate patterns during the learning process. The goal of the current proposal is to elucidate the role of Ca2+/calmodulin protein kinase II (CaMKII) in this type of activity-dependent synaptic plasticity and in memory formation. Stimulation of CaMKII in the hippocampus, a structure important for memory formation in both human beings and experimental animals, alters the ability of neurons to undergo two forms of activity-dependent synaptic plasticity: long-term potentiation (LTP) and long-term depression (LTD). A novel genetic approach will be used to express an activated Ca2+-independent mutant CaMKII transgene in both an anatomically and temporally regulated manner in order to test several hypotheses regarding CaMKII function in LTP and memory storage.
In Aim 1 the effect of CaMKII activation on the stimulation frequency required to produce either LTP or LTD will be determined, and the underlying mechanism of any change will be explored.
In Aim 2 the hypothesis that activated CaMKII exerts its effect on synaptic plasticity and memory by altering calmodulin availability will be tested.
In Aim 3 the hypothesis that LTP in the 5-10 Hz frequency range is required for learning, memory consolidation and/or memory recall will be tested. Finally, in Aim 4 the role of the hippocampus in mediating the learning and memory defects will be determined. These experiments will provide insight into the role of CaMKII and LTP in memory formation, which might allow the development of pharmacological interventions for the treatment of various pathological conditions which affect memory.
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