Abstract
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.
Highlights
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
Briggman et al (2011) reconstructed the starburst-direction-selective ganglion cells (DSGCs) circuitry using serial block-face electron microscopy (SBEM) and observed a prominent asymmetry in their synaptic connectivity[25] (Fig. 1b). They noted that the majority (~90%) of the large “wraparound” synaptic contacts made by radiating starburst dendrites arise from cells that have their somas displaced toward the “null-side” of the DSGC’s receptive field
The skewed distribution of “nullconnections” provides the structural basis for the asymmetric GABAergic inhibition observed in DSGCs, which endows them with direction selectivity[27,28,29,30,31,32] (Fig. 1b)
Summary
Correlations in sEPSC activity as a ratio of the peak amplitudes of the STA and the average sEPSC. Signals measured in small regions of interest in DSGC dendrites (ROIs, identified by mapping regions over which noise was correlated; see “Methods”) were tuned for different directions (Fig. 7a, c, d, e; direction selectivity index [DSI] = 0.35 ± 0.01; n = 723 ROIs; See Eq (4)), indicating that ACh release from varicosities was directional, similar to the Ca2+ responses observed in starburst varicosities using two-photon imaging[33,34]. In this experiment, ACh signals were only measured from dendrites of single ON-OFF DSGCs that were loaded with a red indicator (Alexa 594) through a patch-electrode prior to the imaging session. The lack of global order in the strength of local cholinergic responses, along with the random distribution of the direction tuning, argues against the idea that cholinergic excitation is biased toward the DSGC’s preferred direction[27,46]
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