title: Activation of Glycogen Synthase Kinase-3 Mediates the Olfactory Deficit-Induced Hippocampal Impairments.
abstract: 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-3β (GSK-3β), 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-3β ameliorated the OBX-induced memory deficits with recovery of the synaptic components and tau phosphorylation. Furthermore, genetic ablation of GSK-3β 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.
authors.affiliation: 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.|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.
authors.forename: Juan
authors.initials: J
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: He-Zhou
authors.initials: HZ
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Ao-Ji
authors.initials: AJ
authors.lastname: Xie
authors.affiliation: 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.
authors.forename: Xiong
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Ling-Qiang
authors.initials: LQ
authors.lastname: Zhu
mesh_terms: D000818:Animals; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000201:enzymology*; D007211:Indoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008301:Maleimides / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D066194:Olfactory Cortex / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D057907:Post-Synaptic Density / Q000378:metabolism; D017207:Rats, Sprague-Dawley
chemical_list: D007211:Indoles; D008301:Maleimides; C417521:SB 216763; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3
keywords: Alzheimer’s disease; Bilateral olfactory bulbectomy; Glycogen synthase kinase-3; Hippocampus; Memory deficits