Rapamycin improves social and stereotypic behavior abnormalities induced by pre-mitotic neuronal subset specific Pten deletion

IF 2.4 4区 心理学 Q2 BEHAVIORAL SCIENCES
David A. Narvaiz, Suzanne O. Nolan, Gregory D. Smith, Andrew J. Holley, Conner D. Reynolds, Katherine J. Blandin, Phuoc H. Nguyen, Doan L. K. Tran, Joaquin N. Lugo
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Abstract

The mechanistic target of rapamycin (mTOR) pathway is a signaling system integral to neural growth and migration. In both patients and rodent models, mutations to the phosphatase and tensin homolog gene (PTEN) on chromosome 10 results in hyperactivation of the mTOR pathway, as well as seizures, intellectual disabilities and autistic behaviors. Rapamycin, an inhibitor of mTOR, can reverse the epileptic phenotype of neural subset specific Pten knockout (NS-Pten KO) mice, but its impact on behavior is not known. To determine the behavioral effects of rapamycin, male and female NS-Pten KO and wildtype (WT) mice were assigned as controls or administered 10 mg/kg of rapamycin for 2 weeks followed by behavioral testing. Rapamycin improved social behavior in both genotypes and stereotypic behaviors in NS-Pten KO mice. Rapamycin treatment resulted in a reduction of several measures of activity in the open field test in both genotypes. Rapamycin did not reverse the reduced anxiety behavior in KO mice. These data show the potential clinical use of mTOR inhibitors by showing its administration can reduce the production of autistic-like behaviors in NS-Pten KO mice.

Abstract Image

雷帕霉素改善有丝分裂前神经元亚群特异性Pten缺失引起的社会和刻板行为异常
雷帕霉素(mTOR)通路的机制靶点是神经生长和迁移不可或缺的信号系统。在患者和啮齿动物模型中,10号染色体上磷酸酶和紧张素同源基因(PTEN)的突变导致mTOR通路的过度激活,以及癫痫发作、智力残疾和自闭症行为。雷帕霉素是一种mTOR抑制剂,可以逆转神经亚群特异性Pten敲除(NS-Pten KO)小鼠的癫痫表型,但其对行为的影响尚不清楚。为了确定雷帕霉素的行为影响,将雄性和雌性NS-Pten KO和野生型(WT)小鼠作为对照或给予10 mg/kg雷帕霉素2周,然后进行行为测试。雷帕霉素改善了NS-Pten KO小鼠的社会行为和刻板行为。雷帕霉素治疗导致两种基因型在野外试验中几种活性指标的降低。雷帕霉素并没有逆转KO小鼠焦虑行为的减少。这些数据表明mTOR抑制剂可以减少NS-Pten KO小鼠自闭症样行为的产生,从而显示了mTOR抑制剂的潜在临床应用。
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来源期刊
Genes Brain and Behavior
Genes Brain and Behavior 医学-行为科学
CiteScore
6.80
自引率
4.00%
发文量
62
审稿时长
4-8 weeks
期刊介绍: Genes, Brain and Behavior was launched in 2002 with the aim of publishing top quality research in behavioral and neural genetics in their broadest sense. The emphasis is on the analysis of the behavioral and neural phenotypes under consideration, the unifying theme being the genetic approach as a tool to increase our understanding of these phenotypes. Genes Brain and Behavior is pleased to offer the following features: 8 issues per year online submissions with first editorial decisions within 3-4 weeks and fast publication at Wiley-Blackwells High visibility through its coverage by PubMed/Medline, Current Contents and other major abstracting and indexing services Inclusion in the Wiley-Blackwell consortial license, extending readership to thousands of international libraries and institutions A large and varied editorial board comprising of international specialists.
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