Traditionally, we have viewed neurotransmitter release as being strictly confined to presynaptic active zones and postsynaptic densities. New work by Coggan, Bartol and colleagues, using a combination of high-resolution electron microscopy and computational simulations, indicates that additional neurotransmitter release distant from these sites (ectopic neurotransmitter release) is necessary to activate certain receptors.

Recent work in the chick ciliary ganglion has shown that one class of nicotinic acetylcholine receptor (nAChR) — the α7-nAChRs, which are located on spines — is virtually absent from the postsynaptic density. Nevertheless, these receptors account for numerous changes in physiological measurements, which indicates that they must be involved in neurotransmitter responses. Furthermore, electron microscopy has shown presynaptic vesicles that are ready for neurotransmitter release and fusing vesicles at locations distant from the postsynaptic density. However, until now, there has been no experimental confirmation of ectopic neurotransmitter release during synaptic transmission.

Coggan, Bartol and co-workers used electron microscopy studies to create a geometrically accurate three-dimensional model of a ciliary ganglion synapse, and, on the basis of previous work, incorporated into the model information about the distribution and kinetic properties of presynaptic release sites, acetylcholinesterase and α7-nAChRs. They simulated miniature excitatory postsynaptic currents (mEPSCs) by imitating vesicle release at numerous sites, including postsynaptic density and non-postsynaptic density regions, while simultaneously varying the amount of acetylcholine released into the synaptic cleft.

The simulated mEPSCs most closely resembled previously recorded mEPSCs from a ciliary ganglion in situ when the model included a high proportion of neurotransmitter release that occurred away from the postsynaptic density. By contrast, simulations in which vesicle fusion was limited to the postsynaptic density, or when α7-nAChRs were included in the postsynaptic density, elicited mEPSCs that were at odds with the experimental recordings.

This intriguing finding challenges previous assumptions about the structure and function of synapses. So far, the reason for ectopic neurotransmitter release specifically in the ciliary ganglion is unclear, but the authors speculate that it might relate to the specialized molecular and physiological properties of α7-nAChRs. It will be interesting to determine whether this mechanism for neurotransmitter release is exclusive to the ciliary ganglion or whether it occurs during the activation of other types of receptor.