Role of UBE3A in the Central Nervous System

项目摘要 尽管自闭症和神经发育障碍的遗传异质性 综合征与自闭症合并症，这些之间存在表型趋同， 疾病，导致认为这可能反映了一个共同的病理收敛 大脑皮层回路一个主要的理论表明，兴奋性与兴奋性的比率增加， 抑制性（E/I）神经传递（即，E/I失衡） 导致了自闭症的常见表现型特征为了获得基因的立足点， 了解E/I失衡，我们专注于与自闭症相关的自闭症障碍， 一个基因UBE3A的改变UBE3A表达缺失导致Angelman 综合征（AS），其特征是言语缺失，认知障碍， 癫痫和自闭症的高共病率我们最近证明了抑制性 在AS的小鼠模型中，对皮质锥体神经元的驱动严重减少， 导致E/I比升高。我们的初步数据使我们假设E/I 由UBE 3A蛋白缺失引起的不平衡反映了突触前缺陷， 抑制性中间神经元和锥体神经元中的突触后缺陷。我们进一步 假设UBE 3A功能是维持皮质E/I平衡所必需的， 因此，我们预测，即使在成年人中，UBE3A的缺失也会增加癫痫发作， 与E/I比值升高相关的易感性和认知缺陷。而且我们 假设Ube3a表达恢复将恢复皮质E/I平衡， 逆转某些AS表型。在这个建议中，我们的目标是（1）阐明细胞基础 AS患者皮质E/I失衡;（2）检验Ube3a表达与AS患者皮质E/I失衡的关系。 维持皮质E/I平衡和神经典型行为所需的整个生命周期;（3） 定义AS表型的治疗窗口。我们的研究将有助于建立 AS和可能的其他自闭症谱系的治疗干预参数 紊乱

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.