title: Overactivation of NR2B-containing NMDA receptors through entorhinal-hippocampal connection initiates accumulation of hyperphosphorylated tau in rat hippocampus after transient middle cerebral artery occlusion.
abstract: Middle cerebral artery occlusion (MCAO) induces secondary damages in the hippocampus that is remote from primary ischemic regions. Tau hyperphosphorylation is an important risk for neurodegenerative diseases. Increased tau phosphorylation has been identified in ischemic cortex, but little is known regarding the changes in the hippocampus. We showed that unilateral transient MCAO induced accumulation of hyperphosphorylated tau and concurrent dephosphorylation of glycogen synthase kinase-3β at Ser 9 in the ipsilateral hippocampus. These MCAO-induced changes were not reproduced when glutamatergic inputs from the entorhinal cortex to the hippocampus were transected; however, the changes were mimicked by intrahippocampal N-methyl-d-aspartate (NMDA) administration. Inhibition of NMDA receptor (NMDAR) subunit NR2B, but not NR2A activity in the hippocampus attenuated the accumulation of hyperphosphorylated tau and spatial cognitive impairment in MCAO rats. Together, our data suggest that overactivation of NR2B-containing NMDARs through entorhinal-hippocampal connection plays an important role in the accumulation of hyperphosphorylated tau in the hippocampus following MCAO. Glycogen synthase kinase-3β is an important protein kinase involved in NMDARs-mediated tau hyperphosphorylation. This study indicates that early inhibition of NR2B-containing NMDARs may represent a potential strategy to prevent or delay the occurrence of post-stroke dementia. Middle cerebral artery occlusion induces secondary damage in the hippocampus that is remote from primary ischemic regions. We propose that excessive activation of NR2B-containing NMDA receptors through entorhinal-hippocampal connection initiated the accumulation of hyperphosphorylated tau in the hippocampus, which subsequently induced cognitive deficit. This study provides new insights into the prospects of NR2B inhibition in stoke therapy.
authors.affiliation: Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
authors.forename: Cheng-Shi
authors.initials: CS
authors.lastname: Xu
authors.affiliation: Department of Physiology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei, China.
authors.forename: An-Chun
authors.initials: AC
authors.lastname: Liu
authors.affiliation: Department of Physiology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Pan
authors.affiliation: Department of Physiology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wan
authors.affiliation: Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.|Cerebral Vascular Diseases Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Li
authors.affiliation: Department of Physiology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei, China.
authors.forename: Ze-Fen
authors.initials: ZF
authors.lastname: Wang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018728:Entorhinal Cortex / Q000378:metabolism; D007839:Functional Laterality / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009434:Neural Pathways / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C489131:Mapt protein, rat; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D016875:tau Proteins
keywords: NMDA receptor; hippocampus; ischemia; tau