Increased GHS-R1a expression in the hippocampus impairs memory encoding and contributes to AD-associated memory deficits

• Published in: Communications biology 2024-10, Vol.7 (1), p.1334-16, Article 1334
• Main Authors: Zhang, Meng, Yang, Liu, Jia, Jiajia, Xu, Fenghua, Gao, Shanshan, Han, Fubing, Deng, Mingru, Wang, Jiwei, Li, Vincent, Yu, Ming, Sun, Yuxiang, Yuan, Haicheng, Zhou, Yu, Li, Nan
• Format: Article
• Language: English
• Subjects: 14/19; 14/32; 14/35; 631/378/1595/1554; 631/378/2591/2592; 64/110; 64/60; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Animal models; Animals; Biomedical and Life Sciences; Cognitive ability; Disease Models, Animal; Excitability; Ghrelin; Growth hormones; Hippocampus; Hippocampus - metabolism; Life Sciences; Male; Memory; Memory Disorders - etiology; Memory Disorders - genetics; Memory Disorders - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurodegenerative diseases; Presenilin 1; Pyramidal cells; Pyramidal Cells - metabolism; Receptors, Ghrelin - genetics; Receptors, Ghrelin - metabolism; Spatial memory
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-024-06914-y

Growth hormone secretagogue receptor 1a (GHS-R1a), also known as the ghrelin receptor, is an important nutrient sensor and metabolic regulator in both humans and rodents. Increased GHS-R1a expression is observed in the hippocampus of both Alzheimer’s disease (AD) patients and AD model mice. However, the causal relationship between GHS-R1a elevation in the hippocampus and AD memory deficits remains uncertain. Here, we find that increasing GHS-R1a expression in dCA1 pyramidal neurons impairs hippocampus-dependent memory formation, which is abolished by local administration of the endogenous antagonist LEAP2. GHS-R1a elevation in dCA1 pyramidal neurons suppresses excitability and blocks memory allocation in these neurons. Chemogenetic activation of those high GHS-R1a neurons during training rescues GHS-R1a overexpression-induced memory impairment. Moreover, we demonstrate that increasing GHS-R1a expression in dCA1 pyramidal neurons hampers these neurons’ ability to encode spatial memory and reduces engram size in the dCA1 region. Finally, we show that GHS-R1a deletion mitigates spatial memory deficits in APP/PS1 mice with increased GHS-R1a expression in the hippocampus. Our findings reveal a negative, causal relationship between hippocampal GHS-R1a expression and memory encoding, and suggest that blocking the abnormal increase in GHS-R1a activity/expression may be a promising approach to improve memory and treat cognitive decline in AD. Mechanistic modeling reveals that increased GHS-R1a expression in hippocampal neurons impairs memory formation, suggesting that targeting GHS-R1a activity could improve memory and mitigate cognitive decline in AD.