阻断IL-6信号对孤独症BTBR小鼠行为学的改善及其机理研究

孤独症是一种严重影响患者社会功能的行为发育障碍疾病，发病率高。现有的药物治疗仅为辅助性的对症治疗措施，尚缺乏针对孤独症核心症状的有效药物。近来的研究表明，神经免疫因素和树突棘病理改变是孤独症发病的重要作用机制。申请人前期研究发现，神经免疫因子白细胞介素-6（IL-6）在孤独症患者脑组织内显著高表达；在小鼠脑内过表达IL-6，可以导致孤独症样行为和树突棘形态学改变。已有研究显示IL-6在孤独症动物模型BTBR小鼠多个脑区的表达增高。本项目拟以BTBR小鼠作为研究对象，通过抗体中和方法局部阻断脑内IL-6信号的表达，采用动物行为学测试观察BTBR小鼠的孤独症样行为是否改善；运用免疫荧光和膜片钳技术分析皮层神经元树突棘的形态、分布和突触传递的改变，初步探讨阻断IL-6信号改善孤独症核心症状的可行性及其机理，以期为治疗孤独症提供新的理论基础和药物靶标。

Autism is highly disabling developmental disorders with a large population prevalence. Although a few pharmacological treatments appear to reduce some associated symptoms, there are no therapeutic options that target the core symptoms of autism. Emerging evidence suggests that aberrant neuroimmune response and dendritic spine pathology, may contribute to phenotypic deficits and may be appropriate targets for pharmacologic intervention. Previous research showed that neuroimmune factor, interleukin (IL)-6, was significantly elevated in the fontal cortex and cerebellum of autistic subjects; mice with elevated IL-6 in the brain displayed many autistic features and an abnormal spine morphology. BTBR T+tf/J (BTBR) is an inbred mouse strain that shows robust behavioral phenotypes with analogies to all three of the diagnostic symptoms of autism and can be used to test putative treatments for autism. Consistently, it has been showed that the levels of IL-6 were elevated in the brains of BTBR mice. In this project, using the BTBR mouse model of autism, the IL-6 signaling will be locally blocked by intracerebroventricular injection of anti-IL-6 receptor antibodies. The behavioral tests including social behaviors, ultrasonic vocalizations and repetitive behaviors will be carried out to analyze whether the autism-like behaviors are modulated. The immunofluorescence techniques and whole-cell patch-clamp recordings will be employed to compare the shape, distribution and synapse transmission of dendritic spine. The goal of this study is to investigate the therapeutic potential and the possible mechanism of blockade of IL-6 signaling in autism.