Abstract
Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a breathing disorder associated with cognitive impairment. However, the mechanisms leading to cognitive deficits in OSAHS remain uncertain. In this study, a mouse model of chronic intermittent hypoxia (CIH) exposures were applied for simulating the deoxygenation-reoxygenation events occurring in OSAHS. The conventional adenosine A1 receptor gene (A1R) knockout mice and the A1R agonist CCPA- or antagonist DPCPX-administrated mice were utilized to determine the precise function of A1R signaling in the process of OSAHS-relevant cognitive impairment. We demonstrated that CIH induced morphological changes and apoptosis in hippocampal neurons. Further, CIH blunted hippocampal long-term potentiation (LTP) and resulted in learning/memory impairment. Disruption of adenosine A1R exacerbated morphological, cellular, and functional damage induced by CIH. In contrast, activation of adenosine A1R signaling reduced morphological changes and apoptosis of hippocampal neurons, promoted LTP, and enhanced learning and memory. A1Rs may up-regulate protein kinase C (PKC) and its subtype PKC-ζ through the activation of Gα(i) improve spatial learning and memory disorder induced by CIH in mice. Taken together, A1R signaling plays a neuroprotective role in CIH-induced cognitive dysfunction and pathological changes in the hippocampus.
Highlights
Childhood obstructive sleep apnea-hypopnea syndrome (OSAHS) is a disease characterized by repeated episodes of upper airway collapse during sleep which causes hypopneas/apneas that affect children’s health and growth
T8328) were purchased from Sigma Corporation (USA); Hematoxylin and Eosin (HE) staining kit was obtained from Beyotime Institute of Biotechnology (China); 3,3-diaminobenzidine (DAB) was purchased from ZSGB-BIO Corporation (China); Bicinchoninic acid (BCA) protein assay Kit and ECL western blotting detection reagent were purchased from Pierce Corporation (USA); TUNEL assay kit was from Roche Limited (USA); PCR primer was obtained from Invitrogen Company (USA); Rabbit anti-caspase-3 antibody (Cat. 9662), HRP-labeled goat anti-rabbit secondary antibody (Cat. 7074), and HRP-labeled horse anti-mouse secondary antibody (Cat. 7076) were purchased from Cell Signal Technology (USA); Rabbit anti-Syntaxin (Cat. ab188583), rabbit anti-protein kinase C (PKC) (Cat. ab19031), rabbit anti-PKC-ζ (Cat. ab59364), and rabbit antiGα (i; Cat. ab58916) antibodies were obtained from Abcam Company (USA)
Repeatedmeasures analysis of variance (ANOVA) showed that working memory errors (WME), reference memory errors (RME), and total errors (TE) in all groups significantly decreased throughout training sessions (Figures 1A–C)
Summary
Childhood obstructive sleep apnea-hypopnea syndrome (OSAHS) is a disease characterized by repeated episodes of upper airway collapse during sleep which causes hypopneas/apneas that affect children’s health and growth It can occur at any age group, especially in pre-school children, having a prevalence of between 1.2% and 5.7% of the general population (Marcus et al, 2012). Accumulating evidence shows that CIH exposures suppress long-term potentiation (LTP) in hippocampal neurons (Payne et al, 2004; Xie et al, 2010; Wall et al, 2014; Khuu et al, 2019). Taken together, these findings suggest that CIH is involved in the cognitive impairment of OSAHS. The precise mechanism (s) underlying the OSAHS-relevant cognitive dysfunction remains unclear
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