GHS-R1a Deletion Selectively Reduces Inhibitory Drive of Dca1 Pyramidal Neurons to Improve Memory and Prevent LPS-Induced Memory Impairment

Background: GHS-R1a, the receptor for orexigenic hormone ghrelin, is a GPCR widely distributed in brain including the hippocampus. Studies have demonstrated that genetic deletion of GHS-R1a affects learning and memory, suggesting the importance of ghrelin/GHS-R1a signaling in cognitive control. However, current reports are controversial, and the mechanism underlying GHS-R1a modulation of memory is uncertain.Methods: We investigated effect and mechanism of GHS-R1a deletion on neuronal function and memory with a combination of cutting-edge techniques, including genetic knockout, behavioral assay, electrophysiological recording, in situ hybridization, etc.Findings: GHS-R1a deletion facilitated LTP and enhanced hippocampus-dependent memory. GHS-R1a deletion selectively reduced inhibitory synaptic transmission on dCA1 pyramidal neurons. GHS-R1a deletion specifically suppressed intrinsic excitability of GAD67+ interneurons, rather than neighboring pyramidal neurons. GHS-R1a deletion decreased Akt phosphorylation, and Akt activator SC79 in the hippocampus was able to abolish GHS-R1a deletion-induced inhibition of interneuron excitability. More interestingly, GHS-R1a deletion prevented memory impairment induced by intracerebroventricular injection of lipopolysaccharide that was reported to increase GABAergic inhibition on CA1 pyramidal neurons.Interpretations: Our findings reveal a novel mechanism that GHS-R1a deficiency enhances LTP and memory by reducing interneuron excitability and consequently weakening inhibitory drive of hippocampal pyramidal neurons, under both physiological and pathological conditions. Our findings herein support an adverse effect of GHS-R1a involving Akt signaling in hippocampus-dependent memory processes.Funding: This work was supported by NNSFC (Grant no. 32071141 and 91732110), and NSFC of SD province (Grant no. ZR2019ZD34 and 2019GGX101045).Declaration of Interest: The authors declare no competing interests.Ethical Approval: The Chancellor’s Animal Research Committee at Qingdao Universityapproved all animal protocols used in this study, in accordance with National Institutes of Healthguidelines.