Role of UBE3A in the Central Nervous System

描述（由申请人提供）：尽管自闭症和自闭症共病的神经发育综合征存在遗传异质性，但这些疾病之间存在表型趋同，导致人们认为这可能反映了皮层回路中共同的病理趋同。一个领先的理论认为，在新皮层回路中，兴奋性与抑制性（E/I）神经传递的比例增加（即E/I失衡）有助于自闭症的共同表型特征。为了获得理解E/I失衡的遗传立脚点，我们将重点放在与单一基因UBE3A变化相关的自闭症上。UBE3A表达缺失会导致Angelman综合征（AS），其特征是无法说话、认知障碍、癫痫发作，并与自闭症有很高的合并症。我们最近证明，在AS小鼠模型中，皮质锥体神经元的抑制驱动严重减少，导致E/I比率升高。我们的初步数据使我们假设UBE3A蛋白缺失导致的E/I失衡反映了抑制性中间神经元的突触前缺陷和锥体神经元的突触后缺陷。我们进一步假设UBE3A功能是维持皮层E/I平衡所必需的，因此我们预测即使在成人中，UBE3A的缺失也会增加癫痫易感性和与E/I比值升高相关的认知缺陷。此外，我们假设恢复Ube3a表达将恢复皮质E/I平衡并逆转一些AS表型。在本研究中，我们的目标是：(1)阐明AS中皮质E/I失衡的细胞基础；(2)验证Ube3a的表达是维持皮层E/I平衡和神经典型行为所需的假设；(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.