Molecular Mechanisms of Homeostatic Synaptic Plasticity

稳态突触可塑性的分子机制

• 批准号: 8922051
• 负责人: Hengye Man
• 金额: $ 40.93万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8922051
• 关键词: AMPA Receptors; Binding; Biogenesis; Brain; Calcium; Chronic; Clinical Research; Complex; Deacetylase; Development; Disease; Dominant-Negative Mutation; Drug Addiction; Epigenetic Process; Genetic Transcription; Genetic Translation; Glutamates; HDAC1 gene; Health; Histone Deacetylase; Homeostasis; In Vitro; Light; Maintenance; Mediating; Messenger RNA; MicroRNAs; Modification; Molecular; Neurodegenerative Disorders; Neuroglia; Neurons; Play; Process; Property; Proteins; Reagent; Regulation; Research; Role; Small Interfering RNA; Sodium; Specificity; Stroke; Surface; Synapses; Synaptic Transmission; Synaptic plasticity; Time; Translations; Untranslated Regions; Visual Cortex; Work; epigenetic regulation; excitotoxicity; in vivo; interest; neuron development; overexpression; promoter; receptor; relating to nervous system; response; transcription factor

DESCRIPTION (provided by applicant): Neurons are able to restore their activity when challenged by external or internal perturbations. This type of homeostatic plasticity is important for the maintenance of neuronal or network stability during development and normal brain function. During homeostatic synaptic plasticity, chronic suppression of neuronal activity leads to a compensatory increase in synaptically distributed AMPA receptors (AMPARs) and the intensity of synaptic currents. AMPARs are heterotetrameric channels composed of GluA1-4 subunits. Compared to regular GluA2-containing AMPARs that permit only sodium, GluA2-lacking receptors are permeable to both sodium and calcium. GluA2-lacking, calcium-permeable AMPARs (Cp-AMPARs) are formed during neuronal inhibition and are required for the expression of homeostatic plasticity. However, the molecular mechanisms underlying Cp-AMPAR biogenesis during homeostatic regulation remain largely unknown. We have discovered that miR124, a brain-enriched microRNA (miRNA), suppresses GluA2 translation by targeting the 3'-UTR of GluA2 mRNA, leading to the formation of Cp-AMPARs. Importantly, we found that inhibition of miR124 function abolished inactivity-induced homeostatic regulation. Therefore, we hypothesize that inactivity up-regulates miR124 expression via epigenetic modification, resulting in GluA2 translational suppression and formation of Cp-AMPARs, thus leading to the expression of homeostatic synaptic plasticity. In this proposed study, we will investigate the molecular details in the regulation of miR124 expression and the role of miR124 in GluA2 expression and Cp-AMPAR biogenesis. Furthermore, we will investigate the epigenetic control of miR124 expression by the inhibitory transcription factor EVI and its co-factor, the deacetylase HDAC1. More importantly, we will investigate the involvement of miRNA and the EVI transcriptional complex in the expression of homeostatic plasticity in vitro and in vivo. These studies will shed new light on our understanding of neural functional homeostasis and network stability. Elucidation of Cp-AMPAR biogenesis will also have an impact on clinical studies, as Cp-AMPARs have been implicated in disorders such as stroke, ALS and drug addiction.

描述（由申请人提供）：神经元能够在受到外部或内部扰动的挑战时恢复其活动。这种类型的内稳态可塑性对于维持发育过程中神经元或网络的稳定性和正常的脑功能是重要的。在稳态突触可塑性期间，神经元活动的慢性抑制导致突触分布的AMPA受体（ampar）和突触电流强度的代偿性增加。ampar是由GluA1-4亚基组成的异四聚体通道。与常规的只允许钠的含glua2的AMPARs相比，缺乏glua2的受体对钠和钙都是可渗透的。缺乏glua2的钙通透性AMPARs （Cp-AMPARs）在神经元抑制过程中形成，是稳态可塑性表达所必需的。然而，在稳态调节过程中，Cp-AMPAR生物发生的分子机制在很大程度上仍然未知。我们发现miR124，一种脑富集的microRNA (miRNA)，通过靶向GluA2 mRNA的3'-UTR抑制GluA2的翻译，导致Cp-AMPARs的形成。重要的是，我们发现miR124功能的抑制消除了无活性诱导的稳态调节。因此，我们假设不活动通过表观遗传修饰上调miR124的表达，导致GluA2的翻译抑制和Cp-AMPARs的形成，从而导致稳态突触可塑性的表达。在本研究中，我们将研究miR124表达调控的分子细节，以及miR124在GluA2表达和Cp-AMPAR生物发生中的作用。此外，我们将研究抑制转录因子EVI及其辅助因子去乙酰化酶HDAC1对miR124表达的表观遗传控制。更重要的是，我们将在体外和体内研究miRNA和EVI转录复合物在稳态可塑性表达中的作用。这些研究将为我们对神经功能稳态和网络稳定性的理解提供新的思路。阐明Cp-AMPAR的生物发生机制也将对临床研究产生影响，因为Cp-AMPAR与中风、ALS和药物成瘾等疾病有关。