Progress towards understanding risk factor mechanisms in the development of autism spectrum disorders.

IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Amelia Bryers, Cheryl A Hawkes, Edward Parkin, Neil Dawson
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引用次数: 0

Abstract

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.

在了解自闭症谱系障碍发病的风险因素机制方面取得进展。
自闭症谱系障碍(ASD)是一种以社交障碍和认知症状为特征的异质性综合症。目前,可用于帮助自闭症患者控制症状的治疗方案非常有限。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一步。人类基因研究已经发现了影响较小的常见基因变异和罕见的风险基因以及拷贝数变异(CNVs),它们大大增加了患 ASD 的风险。利用基于这些基因变异的啮齿类动物模型进行的反向转化研究为了解 ASD 的生物学基础提供了新的视角。在此,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。这些模型发现,谷氨酸和 GABA 信号传导失调导致的兴奋-抑制神经递质平衡紊乱是一个关键的致病机制。这些模型还提供了血清素能神经递质系统功能失调的新证据,尽管还需要更多的工作来澄清其性质。在大脑网络层面,前额叶皮质(PFC)功能失调的连通性在这些模型中也很明显,这支持了前额叶皮质功能紊乱是 ASD 病因学中的一个关键环节。总之,已发表的数据凸显了临床前 CNV 小鼠模型在 ASD 病因学方面的实用性和宝贵价值。这些模型确定了治疗 ASD 症状的潜在新型治疗靶点的关键病因机制,使它们成为未来药物发现、开发和验证的有用转化模型。
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来源期刊
Biochemical Society transactions
Biochemical Society transactions 生物-生化与分子生物学
CiteScore
7.80
自引率
0.00%
发文量
351
审稿时长
3-6 weeks
期刊介绍: Biochemical Society Transactions is the reviews journal of the Biochemical Society. Publishing concise reviews written by experts in the field, providing a timely snapshot of the latest developments across all areas of the molecular and cellular biosciences. Elevating our authors’ ideas and expertise, each review includes a perspectives section where authors offer comment on the latest advances, a glimpse of future challenges and highlighting the importance of associated research areas in far broader contexts.
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