Role Of Hippocampal Neuronal Intracellular Calcium Overload Mediated By NMDA Receptor In Modulating Cognitive Dysfunction In A Mouse Model Of Chronic Intermittent Hypoxia

Objective; In this study, using a mouse model of chronic intermittent hypoxia (CIH), we aimed to investigate the role of hippocampal intracellular calcium overload in CIH-induced cognitive dysfunction, and exaimine the neuroprotective effect of memantine, a non-competitive NMDA receptor antagonist, in mediating these changes.Methods:45 ICR male mice, (30±2)g weight, were randomly divided into 3 groups: the unhandled control group (UC group, n=15), the chronic intermittent hypoxia (CIH group, n=15) and the pretreatment memantine group (MEM group, n=15). CIH and MEM mice were subjected to intermittent hypoxia while UC mice to room air for 8 h per day during 4 weeks. Mice in the MEM group were pretreated with memantine (5mg/kg) by intraperitoneal injection before the cycle started, and those in the UC group and the CIH group were treated with same volume of physiological saline. Neurobehavioral assessments were performed by Open filed and Morris water maze, [Ca2+]i in hippocampus was evaluate by flow cytometry, the expression of cleaved caspase-3,-9, PARP in hippocampus were detected by Western blotting.Results:Compared with the UC group, CIH mice displayed markedly more locomotor activity in Open filed test (P<0.05), longer mean escape latency and path length (P<0.05), less number of platform crossings (P<0.05) and less percentage of time in target quadrant (P<0.05). Furthermore, exposed to CIH enhanced [Ca2+]i (vs. UC mice, 155.00±6.12 vs.91.90±4.14, P<0.01), and up-regulated the expression of cleaved caspase-3 (P<0.01), cleaved caspase-9 (P<0.01), cleaved PARP (P<0.01) in the hippocampus. While, pre-treatment with memantine significantly decreased hyperlocomotion (P<0.05), attenuated memory deficits (P<0.05), mitigated [Ca2+]i (vs. CIH mice,90.13±3.78 vs.155.00±6.12, P<0.01), decrease the expression of cleaved caspase-3 (P<0.01), cleaved caspase-9 (P<0.01), cleaved PARP (P<0.01) comparing to the CIH group. Conclusion:We demonstrated that exposure to CIH could induce neurobehavioral deficits of mouse, intracellular calcium concentration overload and apoptosis in the hippocampal, which can be attenuated by NMDA receptors antagonist memantine. These findings suggested overactivation of NMDA receptors and the Ca2+ overload may play important role in mediating the CIH-induced neurocognitive deficits and be hopefully serves as an useful strategy for cognitive dysfunction associated with OSAHS.