Figure 1. Translatable metaplasticity concepts.

(A) Distinctions between plasticity and metaplasticity. (Top) Standard synaptic plasticity induction results in a quantitatively greater excitatory postsynaptic potential (EPSP) in response to the same stimulus (small arrow) after plasticity induction. This alteration in synaptic efficacy results in enhanced excitatory synaptic transmission and structural plasticity as illustrated in the pyramidal cell. (Bottom) In contrast, metaplasticity involves a priming stimulus persistently altering the threshold for a change in synaptic efficacy without changing basal synaptic transmission or neuronal morphology. An example is shown where the priming stimulus lowers the threshold for synaptic potentiation, leading to the same plasticity induction event eliciting a quantitatively greater evoked EPSP response and augmented structural plasticity compared to the response elicited without the priming stimulus. (B) Clinical relevance and advantages of targeting metaplastic mechanisms to promote sustained antidepressant effects. Following intravenous administration, ketamine is rapidly eliminated and side effects generally follow these pharmacokinetics. Acute antidepressant effects are typically observed after exposure and can extend for hours or days. Repeated ketamine administration elicits significantly greater antidepressant effects, and these effects typically persist longer than after a single administration [16, 20-22]. A single administration of ketamine leading to an enhanced antidepressant effect in response to the same treatment days later is consistent with the concept of metaplasticity where the first treatment lowers the threshold for persistent alterations in synaptic efficacy and neural morphology. Targeting metaplastic mechanism(s) to yield persistent antidepressant effects presents therapeutic benefits that may enhance patient compliance such as reduced dosing frequency and, thus, adverse responses because the necessity for the drug to be continuously present is eliminated. Created with Biorender.com