Figure 3: Molecular interactions between long-term potentiation and long-term depression.

a | A schematic of electrode placements for induction of input-specific long-term potentiation (LTP) and long-term depression (LTD) in CA1. The hippocampal slices were obtained from 2-week-old rats. The box shows the dendritic region where enzyme activity was assessed. b | LTP can be induced after 60 shocks at 0 mV as shown by the persistent increase in the amplitude of excitatory postsynaptic currents (EPSCs) after stimulus (stim) application (top left). There is no change in response following an LTP stimulus due to washout of unknown constituents that are required for LTP when baseline recording is extended beyond about 10 minutes (top right). De novo LTD can be induced by 300 shocks at -40 mV and becomes evident by a persistent decrease in EPSC amplitude (bottom left). De novo LTD is inhibited — leaving just a transient depression — if an LTP stimulus (delivered after washout of LTP) is applied first (bottom right). c | Glycogen synthase kinase-3 β (GSK3β) is inhibited after an LTP-inducing stimulus (by phosphorylation at ser9), whereas LTD-inducing stimuli have the opposite effect. d | A diagram showing the cellular mechanism for LTD inhibition by LTP. An LTD-inducing stimulus activates protein phosphatase 1 (PP1), which dephosphorylates GSK3β to activate it and permit the induction of LTD. An LTP stimulus activates the phosphoinositide 3-kinase (PI3K)-Akt pathway, which phosphorylates GSK3β to inhibit it, thus preventing LTD. (Note that the LTP stimulus can inhibit LTD without inducing LTP, as the regulation can occur after washout of LTP.) *, significant difference from control; GluN1, NMDAR (N-methyl-D-aspartate receptor) subunit 1; GluN2, NMDAR subunit 2; GluA1, AMPAR subunit 1; GluA2, AMPAR subunit 2. Parts b and c are modified, with permission, from Ref. 77 © (2007) Cell Press.