Beta calcium/calmodulin dependent kinase II and its role in synaptic plasticity, mammalian learning, and memory

Biochemical and genetic studies in the past have indicated the involvement of various kinases, particularly of Calcium/calmodulin-dependent kinase II (CaMKII), in the signaling network responsible for certain changes in the synaptic efficacy, learning, and memory in the mammalian brain. This particular cascade of molecular changes in the synapse includes an influx of Ca ++ through N-methyl D-aspartate receptor (NMDAR) as a key initial event that ultimately activates CaMKII. CaMKII, in turn, phosphorylates various protein substrates in the post-synaptic density as the main effector of mediating molecular changes in the post-synaptic neuron.; The alpha subunit of CaMKII (alphaCaMKII) and its role in the memory processes has been studied extensively; however, the co-constituent of the CaMKII holoenzyme complex in the mammalian brain, namely beta subunit of CaMKII (betaCaMKII), has yet to be scrutinized in vivo. To further elucidate the roles of the above kinases in learning and memory, a pharmacogenetic method of a conditional protein knock-down using modified kinases and unnatural substrate/inhibitors was carried out in this study. An alteration of betaCaMKII activity in freely behaving transgenic mice shows that there is a perturbation of normal hippocampus function, and it results in a long-term memory performance deficit. This effect is restricted to a subpopulation of neurons in the hippocampus based on a temporal onset of transgenic expression, particularly in the cell layer of dentate gyrus (DG) as in situ visualization and electrophysiology show the expression of betaCaMKII-F90G being predominant in DG over other areas of forebrain. It is also demonstrated that such effect of elevated betaCaMKII activity can be reversed using a custom inhibitor, and that the consolidation of long-term memory is sensitive to the alteration of betaCaMKII activity. In addition, a proteome-wide tracing of direct substrates of CaMKII was carried out for an identification of intracellular signaling network components. Using a bulky ATP analog that can only be utilized by the modified kinase, this ensures a selective identification of true and direct substrates of phosphor-transferase reaction, and here describes novel substrates of CaMKII.