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In many parts of the central nervous system, including the retina, it is unclear whether cholinergic transmission is mediated by rapid, point-to-point synaptic mechanisms, or slower, broad-scale 'non-synaptic' mechanisms. Here, we characterized the ultrastructural features of cholinergic connections between direction-selective starburst amacrine cells and downstream ganglion cells in an existing serial electron microscopy data set, as well as their functional properties using electrophysiology and two-photon acetylcholine (ACh) imaging. Correlative results demonstrate that a 'tripartite' structure facilitates a 'multi-directed' form of transmission, in which ACh released from a single vesicle rapidly (~1 ms) co-activates receptors expressed in multiple neurons located within ~1 µm of the release site. Cholinergic signals are direction-selective at a local, but not global scale, and facilitate the transfer of information from starburst to ganglion cell dendrites. These results suggest a distinct operational framework for cholinergic signaling that bears the hallmarks of synaptic and non-synaptic forms of transmission.

A surprisingly large number of neurons throughout the brain are endowed with the ability to co-release both a fast excitatory and inhibitory transmitter. The computational benefits of dual transmitter release, however, remain poorly understood. Here, we address the role of co-transmission of acetylcholine (ACh) and GABA from starburst amacrine cells (SACs) to direction-selective ganglion cells (DSGCs). Using a combination of pharmacology, optogenetics, and linear regression methods, we estimated the spatiotemporal profiles of GABA, ACh, and glutamate receptor-mediated synaptic activity in DSGCs evoked by motion. We found that ACh initiates responses to motion in natural scenes or under low-contrast conditions. In contrast, classical glutamatergic pathways play a secondary role, amplifying cholinergic responses via NMDA receptor activation. Furthermore, under these conditions, the network of SACs differentially transmits ACh and GABA to DSGCs in a directional manner. Thus, mixed transmission plays a central role in shaping directional responses of DSGCs., (Copyright © 2016 Elsevier Inc. All rights reserved.)