title: NMDA receptor agonists reverse impaired psychomotor and cognitive functions associated with hippocampal Hbegf-deficiency in mice.
abstract: BACKGROUND
  Structural and functional changes of the hippocampus are correlated with psychiatric disorders and cognitive dysfunctions. Genetic deletion of heparin-binding epidermal growth factor-like growth factor (HB-EGF), which is predominantly expressed in cortex and hippocampus, also causes similar psychiatric and cognitive dysfunctions, accompanying down-regulated NMDA receptor signaling. However, little is known of such dysfunctions in hippocampus-specific Hbegf cKO mice.
  
  
  RESULTS
  We successfully developed hippocampus-specific cKO mice by crossbreeding floxed Hbegf and Gng7-Cre knock-in mice, as Gng7 promoter-driven Cre is highly expressed in hippocampal neurons as well as striatal medium spiny neurons. In mice lacking hippocampus Hbegf gene, there was a decreased neurogenesis in the subgranular zone (SGZ) of the dentate gyrus as well as down-regulation of PSD-95/NMDA-receptor-NR1/NR2B subunits and related NMDA receptor signaling. Psychiatric, social-behavioral and cognitive abnormalities were also observed in hippocampal cKO mice. Interestingly, D-cycloserine and nefiracetam, positive allosteric modulators (PAMs) of NMDA receptor reversed the apparent reduction in NMDA receptor signaling and most behavioral abnormalities. Furthermore, decreased SGZ neurogenesis in hippocampal cKO mice was reversed by nefiracetam.
  
  
  CONCLUSIONS
  The present study demonstrates that PAMs of NMDA receptor have pharmacotherapeutic potentials to reverse down-regulated NMDA receptor signaling, neuro-socio-cognitive abnormalities and decreased neurogenesis in hippocampal cKO mice.
authors.affiliation: Department of Pharmacology and Therapeutic Innovation, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, 852-8521, Japan. k-sasaki@nagasaki-u.ac.jp.
authors.forename: Keita
authors.initials: K
authors.lastname: Sasaki
authors.affiliation: Department of Pharmacology and Therapeutic Innovation, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, 852-8521, Japan. omotuyi@nagasaki-u.ac.jp.
authors.forename: Olaposi Idowu
authors.initials: OI
authors.lastname: Omotuyi
authors.affiliation: Department of Pharmacology and Therapeutic Innovation, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, 852-8521, Japan. muueda@gmail.com.
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Department of Neurobiology and Behavior, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, 852-8523, Japan. kazuyuki@nagasaki-u.ac.jp.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Shinohara
authors.affiliation: Department of Pharmacology and Therapeutic Innovation, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, 852-8521, Japan. ueda@nagasaki-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ueda
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003071:Cognition / Q000187:drug effects; D000089622:Doublecortin Domain Proteins; D066257:Heparin-binding EGF-like Growth Factor / Q000172:deficiency* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007858:Learning / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology; D055495:Neurogenesis / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism; D012919:Social Behavior
chemical_list: D000089622:Doublecortin Domain Proteins; D066257:Heparin-binding EGF-like Growth Factor; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D021122:Protein Subunits; D011760:Pyrrolidinones; D016194:Receptors, N-Methyl-D-Aspartate; C058876:nefiracetam; D016202:N-Methylaspartate