Role of UBE3A in the Central Nervous System

项目摘要 尽管自闭症和神经发育存在遗传异质性 自闭症共病综合征，它们之间存在表型趋同 紊乱，导致认为这可能反映了一种共同的病理趋同 在大脑皮层环路。一项领先的理论表明，兴奋与兴奋的比率增加 新皮质环路内抑制(E/I)神经传递(即E/I失衡) 导致自闭症的常见表型特征。在基因上获得立足点 了解E/I失衡，我们关注的是一种与 单个基因UBE3A的变化。UBE3A表达缺失导致Angelman 综合征(AS)，其特征是缺乏语言，认知障碍， 癫痫发作，以及自闭症的高度共病。我们最近证明了抑制作用 在AS小鼠模型中，对皮质锥体神经元的驱动严重减少， 导致E/I比值升高。我们的初步数据使我们假设E/I UBE3A蛋白缺失引起的不平衡反映了突触前缺陷 锥体神经元中的抑制性中间神经元和突触后缺陷。我们进一步 假设需要UBE3A功能来维持皮质E/I平衡，以及 因此，我们预测，即使在成年人中，UBE3A的丢失也会增加癫痫发作 易感性和认知缺陷与E/I比值升高有关。此外，我们 假设恢复Ube3a表达将恢复皮质E/I平衡，并 颠倒一些作为表型。在这项建议中，我们的目标是(1)阐明细胞基础 AS皮质E/I失衡的研究；(2)检验Ube3a表达是 终生需要维持皮质E/I平衡和神经典型行为； 定义AS表型的治疗窗口。我们的研究将有助于确定 AS和可能的其他自闭症谱系的治疗干预参数 精神错乱。

Project Summary Despite the genetic heterogeneity underlying autism and neurodevelopmental syndromes with autism comorbidity, there is phenotypic convergence among these disorders, leading to the view that this may reflect a common pathological convergence in cortical circuits. A leading theory suggests that an increased ratio of excitatory to inhibitory (E/I) neurotransmission (i.e., E/I imbalance) within neocortical circuits contributes to the common phenotypic features of autism. To gain a genetic toehold for understanding E/I imbalance, we have focused on an autism disorder associated with changes in a single gene, UBE3A. Loss of UBE3A expression causes Angelman syndrome (AS), which is characterized by an absence of speech, cognitive disability, seizures, and a high comorbidity with autism. We recently demonstrated that inhibitory drive onto cortical pyramidal neurons is severely decreased in a mouse model of AS, resulting in an elevated E/I ratio. Our preliminary data led us to hypothesize that the E/I imbalance caused by loss of UBE3A protein reflects both presynaptic defects in inhibitory interneurons and postsynaptic defects in pyramidal neurons. We further hypothesize that UBE3A function is required to maintain cortical E/I balance, and therefore we predict that loss of UBE3A even in adults will increase seizure susceptibility and cognitive deficits associated with elevated E/I ratio. Furthermore, we hypothesize that reinstatement of Ube3a expression will restore cortical E/I balance and reverse some AS phenotypes. In this proposal we aim to (1) Elucidate the cellular basis of cortical E/I imbalance in AS; (2) Test the hypothesis that Ube3a expression is required throughout life to maintain cortical E/I balance and neurotypical behaviors; (3) Define treatment windows for AS phenotypes. Our research will help establish parameters for therapeutic interventions in AS and possibly other autism spectrum disorders.