Center for Drug Discovery, RTI International, Research Triangle Park, NC, USA.
Department of Psychiatry and Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Behav Brain Res. 2021 Feb 26;400:113059. doi: 10.1016/j.bbr.2020.113059. Epub 2020 Dec 11.
The G-protein-coupled receptor APLNR and its ligands apelin and ELABELA/TODDLER/apela comprise the apelinergic system, a signaling pathway that is critical during development and physiological homeostasis. Targeted regulation of the receptor has been proposed to treat several important diseases including heart failure, pulmonary arterial hypertension and metabolic syndrome. The apelinergic system is widely expressed within the central nervous system (CNS). However, the role of this system in the CNS has not been completely elucidated. Utilizing an Aplnr knockout mouse model, we report here results from tests of sensory ability, locomotion, reward preference, social preference, learning and memory, and anxiety. We find that knockout of Aplnr leads to significant effects on acoustic startle response and sex-specific effects on conditioned fear responses without significant changes in baseline anxiety. In particular, male Aplnr knockout mice display enhanced context- and cue-dependent fear responses. Our results complement previous reports that exogenous Apelin administration reduced conditioned fear and freezing responses in rodent models, and future studies will explore the therapeutic benefit of APLNR-targeted drugs in rodent models of PTSD.
G 蛋白偶联受体 APLNR 及其配体 apelin 和 ELABELA/TODDLER/apela 组成了阿片肽能系统，这是一种在发育和生理稳态过程中至关重要的信号通路。靶向调节该受体被提议用于治疗多种重要疾病，包括心力衰竭、肺动脉高压和代谢综合征。阿片肽能系统在中枢神经系统 (CNS) 中广泛表达。然而，该系统在 CNS 中的作用尚未完全阐明。利用 Aplnr 基因敲除小鼠模型，我们在此报告了对感觉能力、运动、奖励偏好、社交偏好、学习和记忆以及焦虑的测试结果。我们发现 Aplnr 的敲除导致对声惊反射的显著影响，以及对条件性恐惧反应的性别特异性影响，而基础焦虑没有明显变化。特别是，雄性 Aplnr 基因敲除小鼠表现出增强的上下文和线索依赖性恐惧反应。我们的结果补充了先前的报告，即外源性 Apelin 给药可减少啮齿动物模型中的条件性恐惧和冻结反应，未来的研究将探索 APLNR 靶向药物在 PTSD 啮齿动物模型中的治疗益处。
