Intrinsically photosensitive retinal ganglion cells (ipRGCs) exhibit melanopsin-dependent light responses that persist in the absence of rod and cone photoreceptor-mediated input. In addition to signaling anterogradely to the brain, ipRGCs signal retrogradely to intraretinal circuitry via gap junction-mediated electrical synapses with amacrine cells (ACs). However, the targets and functions of these intraretinal signals remain largely unknown. Here, in mice of both sexes, we identify circuitry that enables M5 ipRGCs to locally inhibit retinal neurons via electrical synapses with a nonspiking GABAergic AC. During pharmacological blockade of rod- and cone-mediated input, whole-cell recordings of corticotropin-releasing hormone-expressing (CRH⁺) ACs reveal persistent visual responses that require both melanopsin expression and gap junctions. In the developing retina, ipRGC-mediated input to CRH⁺ ACs is weak or absent before eye opening, indicating a primary role for this input in the mature retina (i.e., in parallel with rod- and cone-mediated input). Among several ipRGC types, only M5 ipRGCs exhibit consistent anatomical and physiological coupling to CRH⁺ ACs. Optogenetic stimulation of local CRH⁺ ACs directly drives IPSCs in M4 and M5, but not M1-M3, ipRGCs. CRH⁺ ACs also inhibit M2 ipRGC-coupled spiking ACs, demonstrating direct interaction between discrete networks of ipRGC-coupled interneurons. Together, these results demonstrate a functional role for electrical synapses in translating ipRGC activity into feedforward and feedback inhibition of local retinal circuits.

SIGNIFICANCE STATEMENT Melanopsin directly generates light responses in intrinsically photosensitive retinal ganglion cells (ipRGCs). Through gap junction-mediated electrical synapses with retinal interneurons, these uniquely photoreceptive RGCs may also influence the activity and output of neuronal circuits within the retina. Here, we identified and studied an electrical synaptic circuit that, in principle, could couple ipRGC activity to the chemical output of an identified retinal interneuron. Specifically, we found that M5 ipRGCs form electrical synapses with corticotropin-releasing hormone-expressing amacrine cells, which locally release GABA to inhibit specific RGC types. Thus, ipRGCs are poised to influence the output of diverse retinal circuits via electrical synapses with interneurons.

本质上感光的视网膜神经节细胞（ipRGC）表现出黑视蛋白依赖性光反应，这种反应在没有视杆细胞和视锥细胞光感受器介导的输入的情况下持续存在。除了向大脑发出顺行信号外，ipRGC 还通过与无长突细胞 (AC) 之间的间隙连接介导的电突触向视网膜内电路发出逆行信号。然而，这些视网膜内信号的目标和功能仍然很大程度上未知。在这里，我们在两种性别的小鼠中发现了使 M5 ipRGC 能够通过电突触与非尖峰 GABA 能 AC 局部抑制视网膜神经元的电路。在药理学阻断视杆细胞和视锥细胞介导的输入期间，表达促肾上腺皮质激素释放激素（CRH ⁺ ）的 AC 的全细胞记录揭示了需要黑视蛋白表达和间隙连接的持续视觉反应。在发育中的视网膜中，在睁眼之前ipRGC介导的CRH ⁺ ACs输入较弱或不存在，表明该输入在成熟视网膜中起主要作用（即与视杆细胞和视锥细胞介导的输入平行）。在几种 ipRGC 类型中，只有 M5 ipRGC 表现出与 CRH ⁺ AC 一致的解剖学和生理学耦合。局部CRH ⁺ AC的光遗传学刺激直接驱动M4和M5中的IPSC，但不驱动M1-M3、ipRGC。 CRH ⁺ AC 还抑制 M2 ipRGC 耦合的尖峰 AC，证明 ipRGC 耦合的中间神经元的离散网络之间存在直接相互作用。总之，这些结果证明了电突触在将 ipRGC 活动转化为局部视网膜回路的前馈和反馈抑制中的功能作用。

意义声明黑视蛋白直接在本质光敏视网膜神经节细胞 (ipRGC) 中产生光反应。通过间隙连接介导的电突触与视网膜中间神经元，这些独特的感光 RGC 也可能影响视网膜内神经元回路的活动和输出。在这里，我们识别并研究了一种电突触回路，原则上可以将 ipRGC 活动与已识别的视网膜中间神经元的化学输出耦合起来。具体来说，我们发现 M5 ipRGC 与表达促肾上腺皮质激素释放激素的无长突细胞形成电突触，无长突细胞局部释放 GABA 以抑制特定的 RGC 类型。因此，ipRGC 有望通过与中间神经元的电突触影响不同视网膜回路的输出。