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

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.

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。

孤独症是一种严重的神经发育障碍性疾病，缺乏针对孤独症核心症状的有效药物。本项目的主要内容是以孤独症模型BTBR小鼠作为研究对象，阻断脑内IL-6信号的表达，观察BTBR小鼠的孤独症样行为是否改善，探讨阻断IL-6信号改善孤独症行为的作用机理。在本研究项目的资助下，研究以孤独症模型BTBR小鼠为对象，项目的主要研究发现包括：⑴用植入式胶囊渗压泵将重组sgp130Fc蛋白导入侧脑室内后，成功抑制了IL-6信号；⑵抑制IL-6信号可以增加孤独症BTBR小鼠的社交行为能力，自我理毛修饰行为有减少的趋势；⑶抑制IL-6信号后孤独症BTBR小鼠皮层神经元兴奋性突触的数目和突触蛋白的表达没有明显改变；⑷抑制IL-6信号对孤独症BTBR小鼠皮层神经元树突棘的密度和突触后致密物的厚度无明显的作用；⑸抑制IL-6信号后孤独症BTBR小鼠皮层神经元突触连接体谷氨酸的释放量明显增加；⑹建立了BTBR小鼠大脑皮层的差异蛋白质表达谱。项目结果提示阻断IL-6信号可能通过调节兴奋性神经递质谷氨酸的传递参与了孤独症BTBR小鼠社交行为的改善。我们的研究结果进一步表明神经免疫反应在孤独症发病机制中具有重要的作用，为治疗孤独症提供了新的理论基础和药物靶标。