title: Lack of JWA Enhances Neurogenesis and Long-Term Potentiation in Hippocampal Dentate Gyrus Leading to Spatial Cognitive Potentiation.
abstract: JWA (Arl6ip5), a homologous gene of glutamate-transporter-associated protein 3-18 (GTRAP3-18) and addicsin, is highly expressed in hippocampus. We generated systemic and neuronal JWA knockout (JWA-KO and JWA-nKO) mice to investigate the influence of JWA deficiency on spatial cognitive performance, process of neurogenesis, and induction of long-term potentiation (LTP) in hippocampal dentate gyrus (DG). In comparison with wild-type (WT) mice and JWA (loxP/loxP) (control of JWA-nKO) mice, 8-week-old JWA-KO mice and JWA-nKO mice showed spatial cognitive potentiation as assessed by Morris water maze test. In hippocampal DG of JWA-nKO mice, either survival and migration or neurite growth of newborn neurons were significantly enhanced without the changes in proliferation and differentiation of stem cells. In addition, the increase of LTP amplitude and the decline of LTP threshold were observed in DG, but not in CA1 region, of JWA-nKO mice compared to control mice. The levels of hippocampal FAK, Akt, and mTOR phosphorylation in JWA-nKO mice were higher than those in control mice. The PI3K or FAK inhibitor could abolish the enhanced neurogenesis and LTP induction in JWA-nKO mice, which was accompanied by disappearance of the spatial cognitive potentiation. The treatment of JWA-nKO mice with 3'-azido-3'-deoxythymidine (AZT), a telomerase inhibitor, suppressed not only the enhanced neurogenesis but also the enhanced LTP induction in DG, but it did not affect the LTP induction in CA1 region. The results suggest that the JWA deficiency through cascading FAK-PI3K-Akt-mTOR pathway increases the newborn neurons and enhances the LTP induction in hippocampal DG, which leads to the spatial cognitive potentiation.
authors.affiliation: Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, 210029, China.|Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, Jiangsu, 210029, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Sha
authors.affiliation: Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, Hanzhong Road 140, Nanjing, Jiangsu, 210029, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, Jiangsu, 210029, China.
authors.forename: Zi-Hong
authors.initials: ZH
authors.lastname: Lu
authors.affiliation: Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, Jiangsu, 210029, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, Jiangsu, 210029, China.
authors.forename: Wei-Jun
authors.initials: WJ
authors.lastname: Qu
authors.affiliation: Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, Hanzhong Road 140, Nanjing, Jiangsu, 210029, China. jwzhou@njmu.edu.cn.
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Zhou
authors.affiliation: Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, 210029, China. lingchen@njmu.edu.cn.|Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, Jiangsu, 210029, China. lingchen@njmu.edu.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003071:Cognition / Q000187:drug effects; D018891:Dentate Gyrus / Q000187:drug effects / Q000502:physiology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D005838:Genotype; D006360:Heat-Shock Proteins; D017774:Long-Term Potentiation / Q000187:drug effects; D026901:Membrane Transport Proteins; D018345:Mice, Knockout; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015215:Zidovudine / Q000494:pharmacology
chemical_list: C464502:Arl6ip5 protein, mouse; D002352:Carrier Proteins; D006360:Heat-Shock Proteins; D026901:Membrane Transport Proteins; D047428:Protein Kinase Inhibitors; D015215:Zidovudine; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Hippocampus; JWA; Long-term potentiation (LTP); Memory; Neurogenesis