Investigation of fragility factors related to cognitive dysfunction and neurodegeneration in animal models of schizophrenia

精神分裂症动物模型认知功能障碍和神经退行性变相关脆性因素的研究

• 批准号: 17390018
• 负责人: NABESHIMA Toshitaka
• 金额: $ 10.02万
• 依托单位: Meijo University (2007)Nagoya University (2005-2006)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390018/
• 关键词: Phencyclidine; Emotional Deficit; Cognitive Deficit; Disrupted-in-schizonhrenia 1; Neurodevelopment; Prefrontal Cortex; NMDA Receptor; Schizophrenia; 前頭前皮質; 神経変性; Cyclophilin D; フェンシクリジン(PCP); グルタミン酸作動性神経; 細胞内情報伝達系(CaMKII); グリア細胞

We attempted to investigate the molecular mechanisms of emotional and cognitive deficits in schizophrenia-like animal models based on dysfunction hypothesis of glutamatergic systems and neurodevelopment. The mice treated with phencyclidine (PCP: a non-competitive NMDA receptor antagonist) repeatedly exhibited emotional and cognitive deficits. The repeated PCP treatment induced an impaired NMDA-CaMKII signaling and decreased spontaneous extracellular glutamate levels in the prefrontal cortex(PFC).We have found that the mice which via in utero gene transfer achieved selective knockdown of DISC1 in pyramidal neurons of the frontal cortex only during the development, showed maturation-dependent deficits in the mesocortical dopaminergic projections and associated behavioral changes relevant to schizophrenia after puberty. This strategy allows simultaneous manipulation of multiple factors during development in a temporally and spatially specific manner and could be applied generally to exploring disease pathways for major mental illnesses with developmental origins.To examine the changes in protein expression after repeated PCP treatment in PFC of mice, we performed proteomic analysis by using fluorescence two-dimensional difference gel electrophoresis (2D-DIGE). Changes in the relative abundance of 9 protein spots were observed in the PCP-treated mice compared to the saline-treated control mice. Seven spots exhibited an increase, but, 2 protein spots were decreased in the PCP-treated mice when compared to the saline-treated mice. Seven spots identified by liquid chromatographyttandem mass spectrometry were grouped into three functional classes; cell signaling (5 spots), protein degradation (1 spot) and energy metabolism (1 spot). These results suggest that altered protein expressions in the PFC may involve in the molecular mechanisms underlying the schizophrenia-like symptoms in repeated PCP-treated mice.

基于谷氨酸能系统和神经发育功能障碍假说，我们试图探讨精神分裂症样动物模型中情绪和认知缺陷的分子机制。用苯环利定（PCP：一种非竞争性NMDA受体拮抗剂）治疗的小鼠反复表现出情绪和认知缺陷。反复的PCP治疗诱导NMDA-CaMKII信号通路受损，并降低前额皮质（PFC）自发细胞外谷氨酸水平。我们发现，仅在发育过程中通过子宫内基因转移实现额叶皮质锥体神经元DISC1选择性敲低的小鼠，在青春期后表现出与精神分裂症相关的中皮质多巴胺能投射和相关行为改变的成熟依赖性缺陷。这一策略允许在发展过程中以时间和空间特定的方式同时操纵多个因素，可以普遍应用于探索具有发育起源的重大精神疾病的疾病途径。为了检测PCP反复处理小鼠PFC后蛋白表达的变化，我们采用荧光二维差异凝胶电泳（2D-DIGE）进行了蛋白质组学分析。与盐处理小鼠相比，pcp处理小鼠中9个蛋白点的相对丰度发生了变化。与盐处理小鼠相比，pcp处理小鼠的7个蛋白点增加，但2个蛋白点减少。液相色谱-质谱法鉴定的7个斑点分为3个功能类；细胞信号（5个点），蛋白质降解（1个点）和能量代谢（1个点）。这些结果表明，PFC蛋白表达的改变可能涉及反复pcp治疗小鼠精神分裂症样症状的分子机制。

项目成果

Long-Lasting Impairment of Associative Learning Is Correlated with a Dysfunction of N-Methyl-d-aspartate-Extracellular Signaling-Regulated Kinase Signaling in Mice after Withdrawal from Repeated Administration of Phencyclidine

• DOI: 10.1124/mol.105.011304
• 发表时间: 2005-12
• 期刊: Molecular Pharmacology
• 影响因子: 3.6
• 作者: T. Enomoto;Y. Noda;A. Mouri;E. Shin;Dayong Wang;R. Murai;K. Hotta;H. Furukawa;A. Nitta;Hyoung‐Chun Kim;T. Nabeshima

Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes

• DOI: 10.1038/sj.mp.4001824
• 发表时间: 2006-06-01
• 期刊: MOLECULAR PSYCHIATRY
• 影响因子: 11
• 作者: Kasahara, T.;Kubota, M.;Kato, T.
• 通讯作者: Kato, T.

An Analog of a Dipeptide-Like Structure of FK506 Increases Glial Cell Line-Derived Neurotrophic Factor Expression through cAMP Response Element-Binding Protein Activated by Heat Shock Protein 90/Akt Signaling Pathway

• DOI: 10.1523/jneurosci.5010-05.2006
• 发表时间: 2006-03
• 期刊: The Journal of Neuroscience
• 作者: X. Cen;A. Nitta;Shin Ohya;Yinglan Zhao;Naoya Ozawa;A. Mouri;D. Ibi;Li Wang;Makiko Suzuki;Kuniaki Saito;Yasutomo Ito;T. Kawagoe;Y. Noda;Yoshihisa Ito;S. Furukawa;T. Nabeshima

Sustained brain-derived neurotrophic factor up-regulation and sensorimotor gating abnormality induced by postnatal exposure to phencyclidine:comparison with its adult treatment

产后苯环己哌啶暴露引起的持续脑源性神经营养因子上调和感觉运动门控异常：与成人治疗的比较

• 发表时间: 2006
• 期刊: J.Neurochem. 99
• 作者: Takahashi;M.;et. al.
• 通讯作者: et. al.

フェンシクリジン連続投与による前頭皮質ドパミンおよびグルタミン酸作動性神経系の機能低下と認知機能障害

持续服用苯环己哌啶导致额叶皮质多巴胺和谷氨酸能神经系统功能下降和认知功能障碍

• 发表时间: 2006
• 作者: 毛利 彰宏;野田 幸裕;野田 明宏;新田 淳美;古川 宏;鍋島 俊隆
• 通讯作者: 鍋島 俊隆