Figure 1. Positive allosteric modulators modulate receptor activity while maintaining spatial and temporal dynamics associated with neurotransmitter release.

Communication between neurons is commonly encoded by neurotransmitter release events emanating from presynaptic terminals resulting in postsynaptic receptor activation (A). Presynaptic activity patterns (B), and the proximity of a receptor from a neurotransmitter release site, both play a key role in determining postsynaptic receptor activity patterns. In receptor populations that are present in the synaptic cleft, the site of neurotransmitter release is sufficiently proximal to the receptor such that each release event may induce receptor activation (C). Receptor populations that are expressed in extrasynaptic or perisynaptic areas, which are further removed from neurotransmitter release sites, may not be exposed to sufficient neurotransmitter levels following a single release event to become active. However these receptors may be activated following bursts of high-frequency activity when neurotransmitter levels are sufficiently elevated to spill out from the synapse (D). Exogenously applied agonists activate receptors with a temporal profile (E) that is very different from presynaptic activity patterns (B) and will activate receptors regardless of their proximity to presynaptic inputs. In the simplest case, positive allosteric modulators (PAMs) of post-synaptic receptors do not affect presynaptic firing rates (F), but potentiate responses to the endogenous neurotransmitter while maintaining temporally and spatially coded information with respect to receptor activity patterns (G and H). This activity-dependence of allosteric modulators can avoid detrimental effects due to excessive receptor activation and preserve complex physiology such as spike-timing dependent plasticity.