PMID- 25367884 OWN - NLM STAT- MEDLINE DCOM- 20160830 LR - 20211021 IS - 1559-1182 (Electronic) IS - 0893-7648 (Linking) VI - 52 IP - 3 DP - 2015 Dec TI - Activation of Glycogen Synthase Kinase-3 Mediates the Olfactory Deficit-Induced Hippocampal Impairments. PG - 1601-1617 LID - 10.1007/s12035-014-8953-9 [doi] AB - The populations with olfactory dysfunction show an increased chance for hippocampus-dependent episodic memory deficit. Although it is known that the olfactory information projects to the hippocampus through entorhinal cortex layer II, the molecular mechanisms linking olfactory deficit to the hippocampus is not understood. Using bilateral olfactory bulbectomy (OBX) as a model, we found that OBX induced memory deficits with activation of several memory-related protein kinases in the hippocampal extracts, including glycogen synthase kinase-3beta (GSK-3beta), protein kinase A (PKA), extracellular-signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), phosphatidylinositol-3-kinase (PI3K), and protein kinase B (PKB). The OBX rats also show suppression of long-term potentiation (LTP); reduction of synapsin I, synaptophysin, NR2A/B, and PSD95; thinner presynaptic active zone and postsynaptic density with enlarged synaptic space; decreased spine numbers and mushroom-type spines; and tau hyperphosphorylation. After injection of SB216763 for several weeks by vena caudalis, selective inhibition of GSK-3beta ameliorated the OBX-induced memory deficits with recovery of the synaptic components and tau phosphorylation. Furthermore, genetic ablation of GSK-3beta by lentivirus-packed shRNA effectively rescued the memory deficits, synaptic disorder, and tauopathy. Our data indicate that GSK-3 activation mediates the olfactory deficits to the hippocampus, and targeting GSK-3 blocks the pathological connection. FAU - Hu, Juan AU - Hu J AD - Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, China-Canada Cooperation Platform on Neurological Disorder, Institute of Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. AD - Department of Oncology, The First College of Clinical Medical Science, China Three Gorges University and Yichang Central People's Hospital, No. 183 Yiling Road, Yichang, Hubei, 443003, China. FAU - Huang, He-Zhou AU - Huang HZ AD - Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, China-Canada Cooperation Platform on Neurological Disorder, Institute of Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. FAU - Wang, Xiang AU - Wang X AD - Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, China-Canada Cooperation Platform on Neurological Disorder, Institute of Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. FAU - Xie, Ao-Ji AU - Xie AJ AD - Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, China-Canada Cooperation Platform on Neurological Disorder, Institute of Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. FAU - Wang, Xiong AU - Wang X AD - Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, China-Canada Cooperation Platform on Neurological Disorder, Institute of Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. FAU - Liu, Dan AU - Liu D AD - Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, China-Canada Cooperation Platform on Neurological Disorder, Institute of Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. FAU - Wang, Jian-Zhi AU - Wang JZ AD - Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, China-Canada Cooperation Platform on Neurological Disorder, Institute of Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. wangjz@mails.tjmu.edu.cn. FAU - Zhu, Ling-Qiang AU - Zhu LQ AD - Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, China-Canada Cooperation Platform on Neurological Disorder, Institute of Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. zhulq@mail.hust.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20141105 PL - United States TA - Mol Neurobiol JT - Molecular neurobiology JID - 8900963 RN - 0 (Indoles) RN - 0 (Maleimides) RN - 0 (SB 216763) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Gsk3b protein, rat) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) SB - IM EIN - Mol Neurobiol. 2015 Dec;52(3):1618. PMID: 25579383 MH - Animals MH - Glycogen Synthase Kinase 3/*metabolism MH - Glycogen Synthase Kinase 3 beta MH - Hippocampus/*enzymology MH - Indoles/*pharmacology MH - JNK Mitogen-Activated Protein Kinases/metabolism MH - Long-Term Potentiation/physiology MH - Male MH - Maleimides/*pharmacology MH - Mitogen-Activated Protein Kinases/*metabolism MH - Olfactory Cortex/*enzymology MH - Phosphatidylinositol 3-Kinases/metabolism MH - Post-Synaptic Density/metabolism MH - Rats, Sprague-Dawley OTO - NOTNLM OT - Alzheimer's disease OT - Bilateral olfactory bulbectomy OT - Glycogen synthase kinase-3 OT - Hippocampus OT - Memory deficits EDAT- 2014/11/05 06:00 MHDA- 2016/08/31 06:00 CRDT- 2014/11/05 06:00 PHST- 2014/09/13 00:00 [received] PHST- 2014/10/20 00:00 [accepted] PHST- 2014/11/05 06:00 [entrez] PHST- 2014/11/05 06:00 [pubmed] PHST- 2016/08/31 06:00 [medline] AID - 10.1007/s12035-014-8953-9 [pii] AID - 10.1007/s12035-014-8953-9 [doi] PST - ppublish SO - Mol Neurobiol. 2015 Dec;52(3):1601-1617. doi: 10.1007/s12035-014-8953-9. Epub 2014 Nov 5.