Role of UBE3A in the Central Nervous System

UBE3A 在中枢神经系统中的作用

• 批准号: 8995135
• 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/8995135
• 关键词: Absence Epilepsy; Address; Adult; Age; Alleles; Angelman Syndrome; Autistic Disorder; Behavior; Behavioral; Cells; Cognition; Cognitive deficits; Comorbidity; Data; Defect; Development; Disease; Epilepsy; Equilibrium; Functional disorder; Gene Dosage; Genes; Genetic; Genetic Heterogeneity; Health; Impaired cognition; Intellectual functioning disability; Interneurons; Ion Channel; Life; Link; Modeling; Mus; Mutation; Neuraxis; Neurodevelopmental Disorder; Neurons; Pathology; Phenotype; Predisposition; Prefrontal Cortex; Proteins; Research; Role; Seizures; Speech; Synapses; Syndrome; Tamoxifen; Testing; Therapeutic; Therapeutic Intervention; Topoisomerase Inhibitors; Ursidae Family; autism spectrum disorder; base; cell type; cognitive disability; hippocampal pyramidal neuron; insight; motor impairment; mouse model; neocortical; nervous system disorder; neurotransmission; neurotransmitter release; novel; postnatal; postsynaptic; presynaptic; recombinase-mediated cassette exchange; social; theories; therapy outcome

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.

描述（由申请人提供）：尽管孤独症和伴有孤独症合并症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，导致认为这可能反映了皮质回路中常见的病理性趋同。一个领先的理论表明，兴奋性与抑制性（E/I）神经传递的比率增加（即，E/I不平衡）在新皮层回路有助于自闭症的共同表型特征。为了获得理解E/I失衡的遗传立足点，我们专注于与单个基因UBE 3A变化相关的自闭症障碍。UBE 3A表达的缺失导致Angelman综合征（AS），其特征在于言语缺失、认知障碍、癫痫发作以及与自闭症的高共病率。我们最近证明，抑制驱动皮质锥体神经元严重减少，在小鼠模型的AS，导致升高的E/I比。我们的初步数据使我们假设，由UBE 3A蛋白丢失引起的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，即使在成人中，UBE 3A的缺失也会增加癫痫发作的易感性和与E/I比值升高相关的认知缺陷。此外，我们假设Ube 3a表达的恢复将恢复皮质E/I平衡并逆转某些AS表型。本研究的目的是：（1）阐明AS中皮质E/I失衡的细胞基础;（2）检验Ube 3a表达在整个生命过程中维持皮质E/I平衡和神经典型行为所必需的假设;（3）定义AS表型的治疗窗口。我们的研究将有助于建立参数的治疗干预AS和可能的其他自闭症谱系障碍。