Evaluation of a model of long-term memory based on the properties of the Ca2+/calmodulin-dependent protein kinase.

1.) This paper further explores the feasibility of a model for long-term memory (Lisman, 1985; Lisman and Goldring, 1988). According to this model, the value of synaptic efficacy of individual synapses is stored locally by the group of Ca2+/calmodulin-dependent protein kinase II molecules contained within the post-synaptic density. 2.) Calculations presented in a previous paper indicate that it is feasible for these kinase molecules to encode information with the stability required for long-term memory. These calculations were based on the assumption that the 30 phosphorylation sites on the enzyme are phosphorylated in a serial fashion, i.e. that the sites are not independent. This paper presents similar calculations based on the alternative assumption that the sites are phosphorylated independently. 3.) Kinase molecules that have been switched "on" undergo a continuous process of dephosphorylation and rephosphorylation. Estimates of the energy consumed by this cycle indicate that the energy required would not make unreasonable demands on neuronal metabolism. The necessity of energy consumption by molecular switches is discussed. 4.) The rate of intramolecular autophosphorylation of the Ca2+/calmodulin dependent kinase implies that the cytoplasmic free Ca2+ concentration must stay elevated for several seconds in order for kinase molecules to switch "on". How such a sustained rise in Ca2+ might be achieved is discussed. 5.) An alternative view is that long-term memory storage involves a change in gene expression. The principal evidence supporting this view is the effect of protein synthesis inhibitors on memory. A model is presented showing that the observed effect of protein synthesis inhibitors does not necessarily imply that information storage is at the level of gene expression. 6.) The distinction between "presynaptic" and "postsynaptic" associative learning mechanisms is discussed. It is concluded that this distinction can be misleading and that the possibility that the underlying mechanisms are similar should not be excluded.