Curriculum in Neurobiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina North Carolina 27599, USA.
J Clin Invest. 2012 Dec;122(12):4544-54. doi: 10.1172/JCI61888. Epub 2012 Nov 12.
Angelman syndrome (AS) is a neurodevelopmental disorder caused by maternal deletions or mutations of the ubiquitin ligase E3A (UBE3A) allele and characterized by minimal verbal communication, seizures, and disorders of voluntary movement. Previous studies have suggested that abnormal dopamine neurotransmission may underlie some of these deficits, but no effective treatment currently exists for the core features of AS. A clinical trial of levodopa (L-DOPA) in AS is ongoing, although the underlying rationale for this treatment strategy has not yet been thoroughly examined in preclinical models. We found that AS model mice lacking maternal Ube3a (Ube3a(m-/p+) mice) exhibit behavioral deficits that correlated with abnormal dopamine signaling. These deficits were not due to loss of dopaminergic neurons or impaired dopamine synthesis. Unexpectedly, Ube3a(m-/p+) mice exhibited increased dopamine release in the mesolimbic pathway while also exhibiting a decrease in dopamine release in the nigrostriatal pathway, as measured with fast-scan cyclic voltammetry. These findings demonstrate the complex effects of UBE3A loss on dopamine signaling in subcortical motor pathways that may inform ongoing clinical trials of L-DOPA therapy in patients with AS.
天使综合征（AS）是一种神经发育障碍，由母源性 E3A（UBE3A）等位基因突变或缺失引起，其特征为语言交流能力差、癫痫发作和运动障碍。先前的研究表明，多巴胺神经递质的异常可能是这些缺陷的基础，但目前尚无针对 AS 核心特征的有效治疗方法。左旋多巴（L-DOPA）治疗 AS 的临床试验正在进行中，尽管这种治疗策略的潜在原理尚未在临床前模型中得到充分研究。我们发现缺乏母源性 Ube3a 的 AS 模型小鼠（Ube3a(m-/p+) 小鼠）表现出与多巴胺信号异常相关的行为缺陷。这些缺陷不是由于多巴胺能神经元缺失或多巴胺合成受损所致。出乎意料的是，使用快速扫描循环伏安法测量时，Ube3a(m-/p+) 小鼠在中脑边缘多巴胺通路中表现出多巴胺释放增加，而在黑质纹状体多巴胺通路中表现出多巴胺释放减少。这些发现表明 UBE3A 缺失对皮质下运动通路中多巴胺信号的复杂影响，这可能为正在进行的 AS 患者 L-DOPA 治疗的临床试验提供信息。
