Study on long-term potentiation of brain hippocampus

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Long-term potentiation of synaptic transmission which was first discovered in 1973 is now considered to be a primary model of human learning and memory. However, its mechanism has not been elucidated, although the molecular events of the phenomenon are supposed to underlie. Several lines of evidence indicated that the stimulation of the N-methyl-D-aspartate (NMDA) glutamate receptor in the postsynaptic cell triggers the long-term potentiation in CAl area of hippocampus and in turn causes the increase in Ca^<2+> influx. The elevation of the intracellular Ca^<2+> concentration results in activation of Ca^<2+>-dependent protein kinases.Among Ca^<2+>-dependent enzymes, CaM kinase II is of particular interest for two major reasons, 1) it is a major component of postsynaptic densities and 2) it is a multimeric holoenzyme, composed of several catalytic subunits, which may be autophosphorylated following activation by calcium and calmodulin and thereby remain active for a prolonged period of time. Among the molecular mechanisms that have been proposed to contribute to long-term potentiation in hippocampus are the activation and autophosphorylation of CaM kinase II. High, but not low frequency stimulation applied to two groups of CAl afferents resulted in a long lasting increase in the Ca^<2+>-independent and total activities of the enzyme as well as an increase in the ratio of Ca^<2+>-independent to total activity. The effect was obtained using two different CaM kinase II substrates, it was observed in hippocampal slices and in hippocampal organotypic cultures, and it could be blocked by preincubation of slices with the NMDA receptor antagonist D-2-amino-5-phosphonopentanoate. Treatment of slices with calyculin A, a phosphatase inhibitor, modified the activity of the enzyme, but long term potentiation could still be induced and a further increase in Ca^<2+>-independent CaM kinase II activity still observed.