Lasting increases or decreases in the strength of glutamate synapses — long-term potentiation (LTP) or depression (LTD) — occur following activity-dependent changes in calcium concentration in the postsynaptic neuron. Paradoxically, both LTP and LTD seem to depend on increases in intracellular calcium. This has led to the proposal that the direction of the change in synaptic strength is determined by the size of the increase in postsynaptic calcium concentration, with progressively higher calcium causing first LTD and then LTP.

Cho et al. have tested this theory in rat perirhinal cortex by using different concentrations of EGTA to buffer activity-dependent increases in intracellular postsynaptic calcium to different degrees. They found that stimulation that would normally cause LTP induced LTD instead if a high concentration of EGTA was present to limit the rise in calcium concentration.

Interestingly, they also found that moderate levels of the buffer would prevent both LTP and LTD. There seems to be a 'neutral zone', between concentrations of calcium that would normally induce LTD and those that would normally induce LTP, where neither takes place. This is reminiscent of the Bienenstock–Cooper–Munro (BCM) model, which proposes that low frequencies of stimulation will cause LTD, moderate frequencies will cause no change in synaptic strength, and high frequencies will cause LTP.

Is the lack of plasticity in this neutral zone the result of LTD and LTP balancing each other out, or are they both absent? Cho et al. tested this by selectively blocking LTD (using the mGlu receptor antagonist MCPG) or LTP (using the protein kinase inhibitor staurosporine) and repeating the experiment. When activity-dependent calcium levels were buffered to the neutral zone levels and LTD was blocked, LTP still did not occur; likewise, blocking LTP under similar levels of calcium buffering failed to uncover LTD.

So it seems that the cessation of LTD as calcium levels rise from low to moderate is independent of the induction of LTP at still higher levels. This raises the possibility that the higher calcium levels required to induce LTP actually inhibit the mechanisms of induction of LTD. Although the full picture of the molecular mechanisms underlying long-term plasticity is far from clear, these data provide another important piece of the jigsaw.