Activation of Dopamine D1 Receptors at the Axon Initial Segment-Like Process of Retinal AII Amacrine Cells Modulates...

Dopamine is an important neuromodulator found throughout the central nervous system that can influence neural circuits involved in sensory, motor, and cognitive functions. In the retina, dopamine is released by specific amacrine cells and plays a role in reconfiguring circuits for photopic vision. This adaptation takes place both in photoreceptors and at postreceptoral sites. The AII amacrine cell, which plays a crucial role for transmission of both scotopic and photopic visual signals, has been considered an important target of dopaminergic modulation, expressed as a change in the strength of electrical coupling mediated by gap junctions between the AIIs. It has been difficult, however, to find clear evidence for expression of dopamine receptors by AII amacrines. Here, we combined injection of fluorescent dye in AIIs with immunolabeling of type 1 dopamine receptors (D1Rs) and made the surprising observation that D1Rs, along with KCNQ2, an M-type K⁺ channel, are expressed at the AII axon initial segment-like process (AII-AIS) that also expresses voltage-gated Na⁺ (Na_v) channels and generates action potentials. With current-clamp recording of AIIs in rat (male, female) retinal slices, we found that D1R activation reduced spike frequency and increased spike threshold. Taken together with experiments using immunolabeling, pharmacological manipulation, and computational modeling, our results suggest that activation of D1Rs on AIIs reduces the intrinsic excitability of these cells, likely mediated by an intracellular signal transduction pathway involving cAMP, PKA, and phosphorylation of Na_v channels in the AII-AIS. These results suggest a novel mechanism for the role of dopamine in retinal adaptation.