<br>自闭症谱系障碍中的多巴胺能失调：来自遗传小鼠模型的见解,Frontiers in Neural Circuits

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自闭症谱系障碍中的多巴胺能失调：来自遗传小鼠模型的见解
Frontiers in Neural Circuits ( IF 3.4 ) Pub Date : 2021-06-21 , DOI: 10.3389/fncir.2021.700968
Polina Kosillo ₁ , Helen S Bateup _{1,

2,

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Affiliation

自闭症谱系障碍 (ASD) 是一种神经发育障碍，其定义是社交互动和沟通的改变，以及重复、受限、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多个大脑区域与 ASD 病理生理学有关。中脑多巴胺系统是多个 ASD 相关大脑区域中细胞和突触功能的重要调节器，通过解剖学和功能上不同的多巴胺能投射。自闭症谱系障碍的多巴胺假说认为，多巴胺能投射途径的失调可能导致自闭症谱系障碍的行为表现，包括社会刺激的奖励值改变、感觉运动处理的变化和运动刻板印象。在这篇综述中，我们研究了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这一观点的支持。我们讨论了支持多巴胺信号改变参与 ASD 的人类文献，包括遗传、脑成像和药理学研究。然后，我们重点研究综合征性神经发育障碍的遗传小鼠模型，其中单基因突变会导致自闭症谱系障碍（ASD）风险增加。我们重点介绍直接检查这些模型中的多巴胺神经元数量、形态、生理学或输出的研究。总体而言，我们发现，在自闭症谱系障碍中多巴胺系统可能失调的观点得到了相当多的支持。然而，似乎没有一致的特征，一些模型显示多巴胺能功能增强，而另一些模型则多巴胺信号传导不足。我们的结论是，多巴胺失调在自闭症谱系障碍中很常见，但具体的变化可能是每种遗传性疾病所特有的，并且可能无法解释自闭症谱系障碍相关表现的全部范围。

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Dopaminergic dysregulation in syndromic autism spectrum disorders: insights from genetic mouse models

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.

更新日期：2021-06-21

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