Fig. 8. A model of the postulated mechanism governing metaplasticity in the CA1 region of the mouse hippocampus.Top, A sliding threshold model of metaplasticity in the hippocampus. The phosphorylation states of RC3 and CaMKII determine the LTD threshold (θ−), the LTP threshold (θ+), and the ceiling at which LTP is saturated. NMDA receptor-mediated events predominate during HFS, causing dephosphorylation of RC3 and phosphorylation of CaMKII, thereby shifting θ− and θ+ to the right. Type I mGluR-mediated events predominate during LFS, leading to phosphorylation of RC3 and dephosphorylation CaMKII, shifting θ− and θ+ to the left. LTP is saturated when RC3 is minimally and CaMKII maximally phosphorylated, placing θ+ at its rightmost limit. When RC3 is maximally phosphorylated and CaMKII minimally so, θ− and θ+ are situated to the far left, and LTD is induced by small levels of basal activity. Bottom, Circuit diagram of pathways governing CaM availability, the frequency–response threshold, and metaplasticity. Blue arrows denote pathways involved in the induction of LTP (high Ca2+). Red arrows denote pathways involved in LTD (medium Ca2+), and green arrows signify steady-state conditions in the resting synapse. Based on mechanistic insights gleaned from in vitroobservations concerning the dissociation kinetics of RC3 and CaM, we mapped a hypothetical network of commonly accepted biochemical pathways that could explain various metaplastic phenomena. Unphosphorylated RC3 acts as a CaM sink when Ca2+ levels are low (green arrows), releases CaM slowly during medium Ca2+ fluxes (red arrows), and releases Ca2+ rapidly during large NMDA-dependent Ca2+ fluxes (blue arrows). In the latter instance, both high- and low-affinity CaM-binding enzymes are activated. High-affinity enzymes include the Ca2+/CaM-dependent phosphatase calcineurin (PP2B) and the CaM-dependent phosphodiesterase (PDE). Low-affinity enzymes comprise CaMKII and adenylyl cyclase (AC). When high levels of Ca2+ are present and CaM is freely available, cAMP is synthesized by adenylyl cyclase faster than it can be hydrolyzed by PDE, resulting in the activation of PKA. Inhibitor 1 (I1) is phosphorylated by PKA faster than it isdephosphorylated by PP2B, resulting in the inhibition of protein phosphatase 1 (PP1). Thus, the accumulation of phosphorylated CaMKII and the activation of PKA are favored, resulting in LTP. As CaM is sequestered by phospho-CaMKII, activation of the high-affinity binders becomes favored over the low-affinity binders, placing an upper limit on LTP. The activities of high-affinity binders are also favored during smaller Ca2+ fluxes (red arrows). In this case, PDE hydrolyzes cAMP faster than adenylyl cyclase creates it, decreasing the rate of inhibitor 1 phosphorylation by PKA. This, along with increased PP2B activity, decreases the phosphorylation state of inhibitor 1, which disinhibits protein phosphatase 1, decreases the phosphorylation state of CaMKII, and results in LTD. When Ca2+ levels are very low, neither low-affinity nor high-affinity binders are favored, and the final equilibrium concentrations of phosphorylated and dephosphorylated CaMKII at resting Ca2+ levels will depend on the CaM-buffering capacity of RC3. Thus, the phosphorylation state of RC3 would determine the degree of potentiation or depotentiation in the resting synapse by setting baseline levels of phospho-CaMKII and PKA activities. The amount of available CaM, which is governed by the phosphorylation states of both RC3 and CaMKII, would determine the kinetics, direction, and magnitude of synaptic responses to subsequent Ca2+ fluxes. The dotted green linesemphasize the notion that significant CaMKII and PKA activities exist in the resting synapse. Phosphorylation of RC3 increases sensitivity to Ca2+ such that the red pathwaysbecome more dominant at basal Ca2+ concentrations and the blue pathways become favored at medium Ca2+ concentrations. Thus, ablation or phosphorylation of RC3 would shift the resting synapse into a state of LTD and displace θ+ to the left. At modest levels of Ca2+, RC3 and CaM dissociate rather slowly, so we would expect RC3 to constrain the speed and magnitude of CaM-dependent reactions. Thus, ablation or phosphorylation of RC3 would tend to amplify Ca2+/CaM-induced shifts in θ+.