The molecular mechanism and behavioral abnormality in autism models

自闭症模型的分子机制和行为异常

• 批准号: 20591426
• 负责人: YASUDA Shin
• 金额: $ 2.58万
• 依托单位: Tokyo Metropolitan Organization for Medical Research
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20591426/
• 关键词: 脳神経疾患; 神経科学; 行動科学

Dendritic filopodia are most abundant during periods of rapid synaptogenesis, but the number of filopodia declines thereafter. When filopodia contact presynaptic sites and form synapses, filopodia convert into dendritic spines. Normal spine formation may underlie learning and memory function, and abnormal spine formation may be associated with the pathogenesis of mental retardation and/or autism.Mutation of tuberous sclerosis complex (TSC)-2 causes a hereditary autistic disorder in tuberous sclerosis. TSC2 has GAP activity towards small GTPase rheb, and TSC2 antagonizes mTOR pathway by stimulation of GTP hydrolysis of rheb. We analyzed Eker rats heterozygous for a mutation in the tsc2 to examine an involvement of TSC pathway in synaptogenesis. TSC2 mutation caused an inhibition of spine formation in cultured hippocampal neurons. A similar abnormality in spine formation was also observed in wild-type neuron expressed with a GTP-bound form of rheb. Thus, the excessive activation of rheb may cause the disturbance of the dendritic spinogenesis. We next attenuated such excessive activity of rheb-mTOR pathway with an mTOR inhibitor rapamycin. Rapamycin suppressed a phosphorylation of mTOR-downstream p70 S6 kinase, but did not increase the spine formation in tsc2-disrupted neurons, indicating that mTOR pathway may not be involved in spinogenesis. To identify another downstream target of rheb, we performed yeast two-hybrid screening and found a rheb-binding protein (RBP). Knockdown of RBP induced the spine formation in tsc2-mutated neurons. Conversely, overexpression of RBP abolished the maturation to spines in wild-type neurons. Furthermore, the expression of dominant-negative rheb reduced the amount of RBP, and increased dendritic spinogenesis in tsc2-mutated neurons. These results suggest that TSC2 may regulate the dendritic spine formation by controling neuronal RBP amount in a rheb-dependent manner.

树突状丝状伪足在快速突触发生期间最丰富，但此后丝状伪足的数量减少。当丝状伪足接触突触前部位并形成突触时，丝状伪足转变为树突棘。正常的脊柱形成可能是学习和记忆功能的基础，而异常的脊柱形成可能与精神发育迟滞和/或自闭症的发病机制有关。结节性硬化症复合体（TSC）-2突变导致结节性硬化症的遗传性自闭症。TSC 2对小GTP酶rheb具有GAP活性，并且TSC 2通过刺激rheb的GTP水解来拮抗mTOR通路。我们分析了Eker大鼠tsc 2突变的杂合子，以检查TSC通路在突触发生中的参与。TSC 2突变可抑制培养的海马神经元棘的形成。在表达GTP结合型rheb的野生型神经元中也观察到类似的棘形成异常。因此，rheb的过度激活可能导致树突棘发生障碍。我们接下来用mTOR抑制剂雷帕霉素减弱rheb-mTOR途径的这种过度活性。雷帕霉素抑制了mTOR下游p70 S6激酶的磷酸化，但没有增加tsc 2破坏的神经元中的棘形成，表明mTOR通路可能不参与棘发生。为了确定rheb的另一个下游靶点，我们进行了酵母双杂交筛选，发现了rheb结合蛋白（RBP）。敲低RBP诱导tsc 2突变神经元形成棘。相反，RBP的过度表达废除了野生型神经元中的棘的成熟。此外，显性负性rheb的表达减少了RBP的量，并增加了tsc 2突变神经元中树突棘的发生。这些结果表明，TSC 2可能通过调控神经元RBP的量，以rheb依赖的方式调节树突棘的形成。

项目成果

Transducing Neuronal Activity into Dendritic Spine Morphology: New Roles for p38 MAP Kinase and N-cadherin

• DOI: 10.1177/1073858408324024
• 发表时间: 2009-02
• 期刊: The Neuroscientist
• 作者: H. Sugiura;Hidekazu Tanaka;Shin Yasuda;T. Takemiya;K. Yamagata

Association of RGS2 variants with panic disorder in a Japanese population.

RGS2 变异与日本人群恐慌症的关联。

• 发表时间: 2011
• 期刊: American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 156
• 作者: Otowa T;Shimada T;Kawamura Y;Sugaya N;Yoshida E;Inoue K;Yasuda S;Liu X;Minato T;Tochigi M;Umekage T;Kasai K;Tanii H;Okazaki Y;Kaiya H;Sasaki T
• 通讯作者: Sasaki T

The role of two Arcadlin splicing variants in synaptic remodeling

两种 Arcadlin 剪接变体在突触重塑中的作用

• 发表时间: 2008
• 作者: Yasuda S;Sugiura H;Maeno-Hikichi Y;Takemiya T;Tanaka H;Yamagata K
• 通讯作者: Yamagata K

発達障害モデル動物における神経細胞樹状突起の形態変化

发育障碍模型动物神经元树突的形态变化

• 发表时间: 2009
• 作者: 瀧上周;安田新;杉浦弘子;吉村好之;竹宮孝子;山内卓;樋野興夫;山形要人
• 通讯作者: 山形要人

発作により発現する神経接着分子Arcadlinのてんかん病態における役割

Arcadlin（一种在癫痫发作时表达的神经粘附分子）在癫痫病理学中的作用

• 发表时间: 2008
• 作者: 安田新;竹宮孝子;杉浦弘子;瀧上周;田中秀和;山形要人
• 通讯作者: 山形要人