Two major forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD) are cellular processes involved in learning and memory. Although they produce opposite effects on synaptic excitability, both LTP and LTD can occur at the same synapse in response to different patterns of activation of NMDA (N-methyl-D-aspartate) receptors. This raises the question of whether specific mechanisms exist to prevent unwanted interference between the two processes. Collingridge and colleagues have now shown that LTP temporarily inhibits subsequent LTD induction at the same synapse and have uncovered a key role for glycogen synthase kinase 3β (GSK3β) in regulating the synaptic response downstream of NMDA receptor activation.

GSK3β has been implicated in neurological disorders such as Alzheimer's disease and mood disorders; however its roles in normal CNS functions have not yet been determined. In this study the authors showed that GSK3β is present in dendritic spines and is associated with AMPA (α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid) receptors, the trafficking of which is believed to be important for changes in synaptic efficiency during LTP and LTD.

To examine a potential role for GSK3β in synaptic plasticity, the authors investigated the effects of inhibition of the enzyme on induction of LTD and LTP in rat hippocampal slices and revealed that GSK3β is essential for NMDA receptor-mediated LTD in this model. Inhibition of LTD by lithium was observed regardless of whether the inhibitor was applied before or after induction of LTD, suggesting that GSK3β might function in LTD maintenance. Furthermore, increased levels of GSK3β activity were associated with LTD induction. GSK3β activity is regulated by the phosphorylation state of a particular residue (Ser9), with dephosphorylation being associated with enhanced activity. Blocking the activity of protein phosphatase 1 reduced the dephosphorylation of Ser9 during LTD, indicating that this enzyme increases GSK3β activity during LTD.

The authors applied stimuli to cultured neurons that resulted in AMPA receptor insertion into the plasma membrane, mimicking events that take place during LTP induction. They showed that these stimuli also decreased AMPA receptor-associated GSK3β activity, suggesting that induction of LTP could inhibit GSK3β and therefore inhibit LTD. Indeed, the authors showed that the induction of LTP in hippocampal slices prevented the subsequent generation of LTD, an effect that lasted up to 1 hour after LTP induction. Blocking NMDA receptor activity abolished LTP-mediated inhibition of LTD, showing that transient activation of NMDA receptors mediates this effect. To investigate the downstream signalling pathways, the authors carried out a series of experiments using selective inhibitors of the phosphatidylinositol 3-kinase (PI3K)–Akt–GSK3β pathway and demonstrated that stimulation of this pathway, which leads to phosphorylation of GSK3β by Akt, is crucial for the prevention of LTD by LTP.

This study increases our understanding of the regulation of synaptic plasticity, showing one way in which prior synaptic activity can influence later synaptic changes. The benefits of such regulatory functions are unknown, but might include the temporary stabilization of synaptic modifications during a period in which the information is further consolidated within the brain. These findings also provide insights into the normal function of GSK3β in the CNS, which might help to uncover its roles in disease.