Role of UBE3A in the Central Nervous System

UBE3A 在中枢神经系统中的作用

• 批准号: 8612194
• 负责人: BENJAMIN D PHILPOT
• 金额: $ 32.13万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8612194
• 关键词: Absence Epilepsy; Address; Adult; Age; Alleles; Angelman Syndrome; Autistic Disorder; Behavior; Behavioral; Cells; Cognition; Cognitive; Cognitive deficits; Comorbidity; Data; Defect; Development; Disease; Epilepsy; Equilibrium; Functional disorder; Gene Dosage; Genes; Genetic; Genetic Heterogeneity; Impaired cognition; Intellectual functioning disability; Interneurons; Ion Channel; Life; Link; Modeling; Mus; Mutation; Neuraxis; Neurodevelopmental Disorder; Neurons; Outcome; Pathology; Phenotype; Predisposition; Prefrontal Cortex; Proteins; Research; Role; Seizures; Speech; Synapses; Syndrome; Tamoxifen; Technology; Testing; Therapeutic; Therapeutic Intervention; Topoisomerase Inhibitors; Ursidae Family; autism spectrum disorder; base; cell type; disability; hippocampal pyramidal neuron; insight; motor impairment; mouse model; neocortical; nervous system disorder; neurotransmission; neurotransmitter release; novel; postnatal; postsynaptic; presynaptic; public health relevance; social; theories

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.

项目概要 尽管自闭症和神经发育障碍背后存在遗传异质性 患有自闭症合并症的综合征，这些之间存在表型趋同 疾病，导致人们认为这可能反映了共同的病理趋同 在皮质回路中。一个主要理论表明，兴奋性与 新皮质回路内的抑制性 (E/I) 神经传递（即 E/I 失衡） 有助于自闭症的共同表型特征。为了获得基因立足点 了解 E/I 失衡后，我们重点关注与以下疾病相关的自闭症： 单个基因 UBE3A 的变化。 UBE3A 表达缺失导致 Angelman 综合症（AS），其特征是无法言语、认知障碍、 癫痫发作，并且与自闭症有很高的合并症。我们最近证明了抑制 在 AS 小鼠模型中，皮质锥体神经元的驱动力严重降低， 导致 E/I 比升高。我们的初步数据使我们假设 E/I UBE3A 蛋白缺失引起的失衡反映了突触前缺陷 抑制性中间神经元和锥体神经元的突触后缺陷。我们进一步 假设需要 UBE3A 功能来维持皮质 E/I 平衡，并且 因此我们预测，即使在成人中，UBE3A 的缺失也会增加癫痫发作的几率 易感性和认知缺陷与 E/I 比率升高相关。此外，我们 假设恢复 Ube3a 表达将恢复皮质 E/I 平衡 逆转某些 AS 表型。在本提案中，我们的目标是 (1) 阐明细胞基础 AS 皮质 E/I 失衡的影响； (2) 检验Ube3a表达量的假设 终生需要维持皮质 E/I 平衡和神经典型行为； (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 失调。