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PD-1 Regulates GABAergic Neurotransmission and GABA-Mediated Analgesia and Anesthesia

ABSTRACT: Summary 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. Graphical Abstract Highlights • Pd1 mRNA and PD-1 protein are widely expressed in spinal cord and brain neurons• GABA-induced currents in CNS neurons are suppressed by PD-1 blockade with Nivolumab• Nivolumab binds neuronal PD-1 to induce ERK activation and GABAergic inhibition• GABA-mediated pain inhibition and anesthesia is impaired after Pd1 deficiency Immunology ; Molecular Biology; Neuroscience

SUBMITTER: Jiang C

PROVIDER: S-EPMC7530307 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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