Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations, and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies, and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.

自闭症谱系障碍 (ASD) 对受影响个体的发展和社会融入有重大影响，是最具遗传性的精神疾病。自闭症谱系障碍（ASD）病例发病率的增加促使人们对潜在神经病理过程的研究工作激增。我们使用两种研究方法（尸检人脑和 ASD 动物模型）概述了 ASD 神经病理学研究的当前发现，并讨论了每种方法的重叠、局限性和意义。自闭症谱系障碍大脑的尸检显示出整体变化，包括灰质和白质紊乱、神经元数量增加、神经元胞体体积减少和神经纤维增多，最后反映了树突棘、脑血管系统和神经胶质细胞密度的变化。皮质和非皮质区域在神经元形态和细胞结构组织方面都显示出区域特异性异常，与前额皮质、梭状回、额岛皮质、扣带皮质、海马、杏仁核、小脑和脑干报告的结果一致。使用动物模型探索与 ASD 表型临床相关的遗传和非遗传因素的影响，部分解决了将神经病理学与潜在病因联系起来的死后人类研究的不足。转基因模型包括基于充分研究的单基因 ASD 基因（NLGN3、NLGN4、NRXN1、CNTNAP2、SHANK3、MECP2、FMR1、TSC1/2）、新兴风险基因（CHD8、SCN2A、SYNGAP1、ARID1B、GRIN2B、DSCAM、TBR1 ）的模型）和拷贝数变异（15q11-q13 缺失、15q13.3 微缺失、15q11-13 重复、16p11.2 缺失和重复、22q11.2 缺失）。特发性 ASD 模型包括模仿 ASD 行为的近交啮齿动物品系，以及通过环境干预（如产前接触丙戊酸钠、母体自身抗体和母体免疫激活）开发的模型。除了复制尸检研究中看到的一些神经病理学特征外，几种 ASD 动物模型的一个常见发现是树突棘密度的改变，改变的方向取决于特定的基因修饰、年龄和大脑区域。总体而言，代表各种 ASD 风险基因和不同临床表型的较大样本量的死后神经病理学研究有必要进一步阐明假定的病因途径，并促进临床相关诊断和治疗工具的出现。此外，由于基因改变可能使某些个体更容易出现自闭症谱系障碍行为表现背后的突触病理变化，因此使用转基因动物模型进行神经病理学研究将有助于提高我们对疾病机制的理解，并促进靶向治疗的开发。治疗。