title: CIH-induced neurocognitive impairments are associated with hippocampal Ca(2+) overload, apoptosis, and dephosphorylation of ERK1/2 and CREB that are mediated by overactivation of NMDARs.
abstract: Chronic intermittent hypoxia (CIH) is commonly seen in patients with obstructive sleep apnea, and has been hypothesized to underlie the neurocognitive dysfunction in these patients. However, its cellular and molecular mechanisms remain to be defined. The present study aimed to investigate, in a mouse CIH model, the role of NMDA receptor (NMDAR) activation in mediating the CIH-induced neurocognitive impairments, caspase expression and dysregulated Ca(2+) signaling pathways in hippocampus. Male ICR mice (n=45) were exposed to CIH (8h/day) or room air (control) for 4 weeks. After 4-week treatment, neurobehavioral assessments were performed by Morris water maze test, hippocampal [Ca(2+)]i was evaluated by flow cytometry; and protein expressions of caspase-3, caspase-9, PARP, p-ERK1/2 and p-CREB in hippocampus were measured by Western blotting. Our results showed that, compared to control animals, 4-week exposure to CIH produced significant spatial learning and memory impairments in CIH mice. Increased caspase expression in hippocampus was observed in CIH mice associated with significant elevation of [Ca(2+)]i and dephosphorylation of ERK and CREB expression. When the NMDAR antagonist memantine was administered by intraperitoneal injection prior to daily exposure to CIH, at a sub-therapeutic dose of 5mg/kg/day not shown to impact the neurobehavioral performance in control animals, the neurocognitive impairments as well as the neurobiochemical changes were abolished or normalized in the CIH mice. Our study suggests that overactivation of NMDARs and the Ca(2+) overload-dependent ERK/CREB dysregulation is one of the important mechanisms in mediating the CIH-induced neurocognitive impairments.
authors: Department of Respiratory Medicine, Sleeping Center, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors: Jing
authors: J
authors: Wang
authors: Department of Respiratory Medicine, Sleeping Center, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors: Hong
authors: H
authors: Ming
authors: Department of Respiratory Medicine, Sleeping Center, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China. Electronic address: chenruigood@126.com.
authors: Rui
authors: R
authors: Chen
authors: Department of Respiratory Medicine, Sleeping Center, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors: Jing-Mei
authors: JM
authors: Ju
authors: Department of Respiratory Medicine, Sleeping Center, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors: Wan-da
authors: WD
authors: Peng
authors: Department of Physiology, Medical College of Soochow University, Suzhou, Jiangsu, China.
authors: Guo-Xing
authors: GX
authors: Zhang
authors: Laboratory of Aging and Nervous Diseases, Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
authors: Chun-Feng
authors: CF
authors: Liu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D050882:CREB-Binding Protein / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D005434:Flow Cytometry; D006624:Hippocampus / Q000378:metabolism*; D000860:Hypoxia / Q000150:complications*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008559:Memantine / Q000627:therapeutic use; D051379:Mice; D008813:Mice, Inbred ICR; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013997:Time Factors
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D050882:CREB-Binding Protein; D002118:Calcium; D008559:Memantine
keywords: Calcium overload; Chronic intermittent hypoxia; Memantine; NMDA; Neurocognitive impairments; Receptors