Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, UK.
Biochem Soc Trans. 2024 Oct 30;52(5):2047-2058. doi: 10.1042/BST20231004.
Autism spectrum disorders (ASD) are a heterogenous set of syndromes characterised by social impairment and cognitive symptoms. Currently, there are limited treatment options available to help people with ASD manage their symptoms. Understanding the biological mechanisms that result in ASD diagnosis and symptomatology is an essential step in developing new interventional strategies. Human genetic studies have identified common gene variants of small effect and rare risk genes and copy number variants (CNVs) that substantially increase the risk of developing ASD. Reverse translational studies using rodent models based on these genetic variants provide new insight into the biological basis of ASD. Here we review recent findings from three ASD associated CNV mouse models (16p11.2, 2p16.3 and 22q11.2 deletion) that show behavioural and cognitive phenotypes relevant to ASD. These models have identified disturbed excitation-inhibition neurotransmitter balance, evidenced by dysfunctional glutamate and GABA signalling, as a key aetiological mechanism. These models also provide emerging evidence for serotoninergic neurotransmitter system dysfunction, although more work is needed to clarify the nature of this. At the brain network level, prefrontal cortex (PFC) dysfunctional connectivity is also evident across these models, supporting disturbed PFC function as a key nexus in ASD aetiology. Overall, published data highlight the utility and valuable insight gained into ASD aetiology from preclinical CNV mouse models. These have identified key aetiological mechanisms that represent putative novel therapeutic targets for the treatment of ASD symptoms, making them useful translational models for future drug discovery, development and validation.
自闭症谱系障碍（ASD）是一组以社交障碍和认知症状为特征的异质性综合征。目前，可用的治疗选择有限，无法帮助 ASD 患者控制其症状。了解导致 ASD 诊断和症状的生物学机制是开发新干预策略的重要步骤。人类遗传研究已经确定了常见的小效应基因变异体和罕见的风险基因和拷贝数变异（CNVs），这些变异体大大增加了 ASD 的发病风险。基于这些遗传变异的啮齿动物模型的反向转化研究为 ASD 的生物学基础提供了新的见解。在这里，我们回顾了三个与 ASD 相关的 CNV 小鼠模型（16p11.2、2p16.3 和 22q11.2 缺失）的最新发现，这些模型显示出与 ASD 相关的行为和认知表型。这些模型确定了兴奋性抑制性神经递质平衡的紊乱，表现为谷氨酸和 GABA 信号功能障碍，这是一个关键的发病机制。这些模型还为 5-羟色胺能神经递质系统功能障碍提供了新的证据，尽管需要更多的工作来阐明其性质。在大脑网络水平上，这些模型也显示出前额叶皮层（PFC）功能连接的紊乱，支持 PFC 功能障碍作为 ASD 发病机制的关键枢纽。总的来说，已发表的数据强调了临床前 CNV 小鼠模型在 ASD 发病机制方面的实用性和有价值的见解。这些模型确定了关键的发病机制，代表了治疗 ASD 症状的潜在新治疗靶点，使其成为未来药物发现、开发和验证的有用转化模型。
