Dopaminergic Dysregulation in Syndromic Autism Spectrum Disorders: Insights From Genetic Mouse Models.
Dopaminergic Dysregulation in Syndromic Autism Spectrum Disorders: Insights From Genetic Mouse Models.
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综合症自闭症谱系疾病中的多巴胺能失调：遗传小鼠模型的见解。
DOI：
10.3389/fncir.2021.700968
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发表时间：
2021
影响因子：
3.5
通讯作者：
Bateup HS
中科院分区：
文献类型：
--
作者：
Kosillo P;Bateup HS
自闭症谱系障碍（ASD）是一种神经发育障碍，其定义为改变的社会互动和交流，以及重复的，受限的，僵化的行为。大约1.5-2%的普通人群符合ASD的诊断标准，并且包括皮质、杏仁核、小脑和基底神经节在内的几个脑区域与ASD病理生理学有关。中脑多巴胺系统是一个重要的调制器的细胞和突触功能在多个ASD牵连的大脑区域通过解剖学和功能上不同的多巴胺能投射。ASD的多巴胺假说假定多巴胺能投射通路的失调可能有助于ASD的行为表现，包括改变社会刺激的奖励值，感觉运动处理的变化和运动刻板。在这篇综述中，我们研究了支持的想法，多巴胺能功能的细胞自主变化是ASD病理生理学的核心组成部分。我们讨论了支持ASD中多巴胺信号改变的人类文献，包括遗传学、脑成像和药理学研究。然后，我们专注于综合征性神经发育障碍的遗传小鼠模型，其中单基因突变导致ASD风险增加。我们强调直接研究多巴胺神经元的数量，形态，生理学，或输出在这些模型中的研究。总的来说，我们发现相当多的支持的想法，多巴胺系统可能是失调的综合征ASD;然而，似乎没有一个一致的签名和一些模型显示增加多巴胺能功能，而其他人有不足的多巴胺信号。我们的结论是，多巴胺失调在自闭症谱系障碍综合征中很常见，但具体变化可能是每种遗传性疾病所独有的，并且可能无法解释自闭症谱系障碍相关表现的全部范围。
Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by altered social interaction and communication, and repetitive, restricted, inflexible behaviors. Approximately 1.5-2% of the general population meet the diagnostic criteria for ASD and several brain regions including the cortex, amygdala, cerebellum and basal ganglia have been implicated in ASD pathophysiology. The midbrain dopamine system is an important modulator of cellular and synaptic function in multiple ASD-implicated brain regions via anatomically and functionally distinct dopaminergic projections. The dopamine hypothesis of ASD postulates that dysregulation of dopaminergic projection pathways could contribute to the behavioral manifestations of ASD, including altered reward value of social stimuli, changes in sensorimotor processing, and motor stereotypies. In this review, we examine the support for the idea that cell-autonomous changes in dopaminergic function are a core component of ASD pathophysiology. We discuss the human literature supporting the involvement of altered dopamine signaling in ASD including genetic, brain imaging and pharmacologic studies. We then focus on genetic mouse models of syndromic neurodevelopmental disorders in which single gene mutations lead to increased risk for ASD. We highlight studies that have directly examined dopamine neuron number, morphology, physiology, or output in these models. Overall, we find considerable support for the idea that the dopamine system may be dysregulated in syndromic ASDs; however, there does not appear to be a consistent signature and some models show increased dopaminergic function, while others have deficient dopamine signaling. We conclude that dopamine dysregulation is common in syndromic forms of ASD but that the specific changes may be unique to each genetic disorder and may not account for the full spectrum of ASD-related manifestations.
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