論文 - 詳細
| RRC ID | 36680 |
|---|---|
| 著者 | Sasaki K, Omotuyi OI, Ueda M, Shinohara K, Ueda H. |
| タイトル | NMDA receptor agonists reverse impaired psychomotor and cognitive functions associated with hippocampal Hbegf-deficiency in mice. |
| ジャーナル | Mol Brain |
| 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. |
| 巻・号 | 8(1) |
| ページ | 83 |
| 公開日 | 2015-12-4 |
| DOI | 10.1186/s13041-015-0176-0 |
| PII | 10.1186/s13041-015-0176-0 |
| PMID | 26637193 |
| PMC | PMC4670538 |
| MeSH | Allosteric Regulation / drug effects Animals Behavior, Animal / drug effects Cognition* / drug effects Doublecortin Domain Proteins Heparin-binding EGF-like Growth Factor / deficiency* Heparin-binding EGF-like Growth Factor / metabolism Hippocampus / drug effects Hippocampus / metabolism* Learning / drug effects Long-Term Potentiation / drug effects Male Mice, Inbred C57BL Mice, Knockout Microtubule-Associated Proteins / metabolism Motor Activity* / drug effects N-Methylaspartate / pharmacology Neurogenesis / drug effects Neuronal Plasticity / drug effects Neurons / metabolism Neuropeptides / metabolism Protein Subunits / metabolism Pyrrolidinones / pharmacology Receptors, N-Methyl-D-Aspartate / agonists* Receptors, N-Methyl-D-Aspartate / metabolism Social Behavior |
| IF | 4.686 |
| 引用数 | 13 |
| WOS 分野 | NEUROSCIENCES |
| リソース情報 | |
| 実験動物マウス | RBRC01308 |