Uncovering the "hidden" synaptic microarchitecture of the retinal direction selective circuit.

GABAergic/cholinergic starburst amacrine cells play a crucial role in shaping direction selectivity in the dendrites of downstream direction-selective (DS) ganglion cells (DSGCs) in the retina by providing "null" inhibitory and "preferred" excitatory signals. The extent to which GABA and acetylcholine (ACh) signals are co-transmitted at the subcellular level is challenging to assess, making it difficult to fully appreciate the mechanisms underlying this dendritic computation. Here, two-photon Ca2+ imaging reveals that processing within local dendritic "DS subunits" is compromised when ACh dynamics are perturbed regionally with an acetylcholinesterase blocker. A network model that captures the specific anatomical "wiring" of the DS circuit reveals how minor perturbations in the spatiotemporal properties of ACh-that do not disrupt the global excitation/inhibition (E/I) balance-uncouple E/I locally and compromise direction selectivity. These results reveal the inner workings of the "hidden" synaptic microarchitecture that mediates diverse, localized direction computations across the DSGC's dendritic field.