Role of UBE3A in the Central Nervous System

描述(申请人提供)：尽管自闭症和伴有自闭症共病的神经发育综合征存在遗传异质性，但这些障碍之间存在表型趋同，导致有观点认为这可能反映了皮质回路中常见的病理趋同。一种领先的理论认为，新皮质环路中兴奋性与抑制性(E/I)神经传递比率的增加(即E/I失衡)是自闭症常见表型特征的原因。为了获得了解E/I失衡的基因立足点，我们将重点放在一种与单基因UBE3A变化相关的自闭症障碍上。UBE3A表达缺失会导致Angelman综合征(AS)，其特征是缺乏言语、认知障碍、癫痫发作，并与自闭症高度共病。我们最近证明，在AS小鼠模型中，对皮质锥体神经元的抑制驱动严重减少，导致E/I比值升高。我们的初步数据使我们假设，UBE3A蛋白缺失引起的E/I失衡既反映了抑制性中间神经元的突触前缺陷，也反映了锥体神经元的突触后缺陷。我们进一步假设，UBE3A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易感性和与E/I比率升高相关的认知障碍。此外，我们假设恢复Ube3a的表达将恢复皮质的E/I平衡，并逆转一些表型。在这项建议中，我们的目标是(1)阐明AS皮质E/I失衡的细胞学基础；(2)检验Ube3a表达是维持皮质E/I平衡和神经典型行为的一生所必需的假设；(3)确定AS表型的治疗窗口。我们的研究将有助于为AS和可能的其他自闭症谱系障碍的治疗干预建立参数。

DESCRIPTION (provided by applicant): 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 contributesto 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.