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Overactivation of NR 2B‐containing NMDA receptors through entorhinal–hippocampal connection initiates accumulation of hyperphosphorylated tau in rat hippocampus after transient middle cerebral artery occlusion
Author(s) -
Xu ChengShi,
Liu AnChun,
Chen Juan,
Pan ZhiYong,
Wan Qi,
Li ZhiQiang,
Wang ZeFen
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13134
Subject(s) - hippocampus , entorhinal cortex , nmda receptor , hippocampal formation , hyperphosphorylation , neuroscience , gsk 3 , glycogen synthase , medicine , phosphorylation , endocrinology , chemistry , receptor , biology , biochemistry , glycogen
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 NR 2B, but not NR 2A activity in the hippocampus attenuated the accumulation of hyperphosphorylated tau and spatial cognitive impairment in MCAO rats. Together, our data suggest that overactivation of NR 2B‐containing NMDAR s 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 NMDAR s‐mediated tau hyperphosphorylation. This study indicates that early inhibition of NR 2B‐containing NMDAR s 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.