The immune checkpoint inhibitor programmed cell death protein 1 (PD-1) plays a critical role in immune regulation. Recent studies have demonstrated functional PD-1 expression in peripheral sensory neurons, which contributes to neuronal excitability, pain, and opioid analgesia. Here we report neuronal expression and function of PD-1 in the central nervous system (CNS), including the spinal cord, thalamus, and cerebral cortex. Notably, GABA-induced currents in spinal dorsal horn neurons, thalamic neurons, and cortical neurons are suppressed by the PD-1-neutralizing immunotherapeutic Nivolumab in spinal cord slices, brain slices, and dissociated cortical neurons. Reductions in GABA-mediated currents in CNS neurons were also observed in Pd1^−/− mice without changes in GABA receptor expression. Mechanistically, Nivolumab binds spinal cord neurons and elicits ERK phosphorylation to suppress GABA currents. Finally, both GABA-mediated analgesia and anesthesia are impaired by Pd1 deficiency. Our findings reveal PD-1 as a CNS-neuronal inhibitor that regulates GABAergic signaling and GABA-mediated behaviors.

免疫检查点抑制剂编程的细胞死亡蛋白1（PD-1）在免疫调节中起关键作用。最近的研究表明，在外周感觉神经元中有功能性PD-1表达，这有助于神经元兴奋性，疼痛和阿片类镇痛。在这里，我们报告PD-1在包括脊髓，丘脑和大脑皮层的中枢神经系统（CNS）中的神经元表达和功能。值得注意的是，在脊髓切片，脑切片和游离皮质神经元中，PD-1中和性免疫治疗药物Nivolumab抑制了GABA诱导的脊髓背角神经元，丘脑神经元和皮质神经元电流。在P d1 ^-/-中也观察到CNS神经元中GABA介导的电流减少。GABA受体表达无变化的小鼠。机械上，Nivolumab结合脊髓神经元并引发ERK磷酸化，从而抑制GABA电流。最后，Pd1缺乏会损害GABA介导的镇痛和麻醉作用。我们的发现揭示了PD-1作为中枢神经系统神经元抑制剂，可调节GABA能信号和GABA介导的行为。