γ-氨基丁酸能系统影响儿童孤独症谱系障碍发生与预后的脑机制研究

Autism spectrum disorders (ASD) occur early in childhood with unknown etiology. Studies have shown that gamma-aminobutyric acid (GABA) and gamma-aminobutyric acid type A (GABAA) receptor genes play important roles in the maintenance of synaptic structures and functions of the brain, but their relationships with ASD are unclear. Previous studies of the project team found that the GABAA receptor genovariation was in connection with the occurrence, the symptom-based and developmental phenotypes and the developmental rehabilitation effects of ASD, which prompted that the defects along with the abnormalities in GABA-ergic system may be related to the abnormalities in brain structures and brain functions. This project will apply case-control study by using the methods of questionnaire investigation, professional assessments as well as laboratory and imaging tests to analyze the revelance of GABA levels, GABAA receptor genovariation, symptom-based and developmental phenotypes as well as brain structures and resting state brain functions between ASD and typical developing (TD) groups; and carry out 1 year’s rehabilitation intervention study on children with ASD to investigate the influences of GABAA receptor genovariation and the baseline of GABA levels on the variation tendency of GABA levels, symptom-based and developmental phenotypes, as well as brain structures and resting state brain functions in children with ASD, so as to comprehensively explore the brain mechanisms for the effects of GABA-ergic system on the occurrence and prognosis of children with ASD, and provide new ideas for the diagnosis, rehabilitation and treatment of children with ASD.

孤独症谱系障碍（ASD）发病于童年早期且病因不明。已有研究显示γ-氨基丁酸（GABA）和γ-氨基丁酸A型（GABAA）受体基因在脑突触结构与功能维持方面具有重要作用，但其与ASD的关系不明。项目组前期研究发现GABAA受体基因变异与ASD的发生、症状与发育表型及发育康复效果有关，提示GABA能系统异常所伴随的缺陷可能与脑结构和脑功能异常有关。本课题将应用病例-对照研究方法，采用问卷调查、专业评估及实验室与影像学检测手段，分析ASD组与正常发育（TD）组的GABA水平、GABAA受体基因变异、症状与发育表型及脑结构和静息态脑功能的相关性；对ASD儿童进行1年的康复干预研究，探讨GABAA受体基因变异和基线GABA水平对ASD儿童的GABA水平、症状与发育表型及脑结构和静息态脑功能变化趋势的影响，全面探讨GABA能系统影响儿童ASD发生与预后的脑机制，为儿童ASD的诊断、康复与治疗提供新思路。

孤独症谱系障碍（ASD）是一组复杂的神经发育障碍，病因可能包括脑生物学因素改变，但发病机制尚未明确。本项目主要围绕γ-氨基丁酸（GABA）能系统-症状与发育表型-脑结构和静息态脑功能对ASD儿童和正常发育（TD）儿童开展研究，主要成果包括：（1）相比TD组，ASD组存在较低的血浆GABA水平和较差的发育水平，以及较高的体质指数、较多的睡眠问题、感觉异常、社交互动异常、沟通异常与重复刻板行为和狭隘的兴趣等。（2）相比TD组，ASD组存在增大和减小的脑灰质体积区域；两组间静息态脑功能的全脑低频振幅、局部一致性（ReHo）、体素-镜像同伦连接信号、度中心性和功能连接也存在差异。（3）ASD儿童的GABA水平越低，则多动越明显、社交互动能力越弱、就寝习惯越差以及大肌肉能力等越弱；TD儿童的GABA水平越高，则社交能力越好。（4）ASD儿童的GABA水平越低，则左顶枕沟旁、右顶枕沟旁和小脑蚓部的灰质体积越大；TD儿童的GABA水平越低，则右中央后回的脑灰质体积越大。（5）ASD儿童的症状和表型与脑灰质体积存在多种关联。（6）经过1年康复干预后的ASD儿童，在睡眠状况、ASD核心症状、认知（语言/语前）、大肌肉和模仿（视觉/动作）等方面都有改善；其静息态脑功能的ReHo在左侧额中回后部显著增高，而在右侧小脑显著降低。本项目不仅有利于寻找帮助ASD进行早期筛查和诊断的脑生物学因素标志物，而且可以采用多途径评价经过康复干预后ASD儿童的康复效果和脑发育改变，为儿童ASD的诊断、康复和治疗提供理论依据。