Molecular Mechanisms of Homeostatic Synaptic Plasticity

描述(申请人提供)：当受到外部或内部干扰时，神经元能够恢复其活动。这种动态平衡的可塑性对于在发育过程中维持神经元或网络的稳定性和正常的大脑功能非常重要。在动态平衡的突触可塑性过程中，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有GluA2的AMPAR相比，缺乏GluA2的受体对钠和钙都是通透的。缺乏GluA2的钙通透性AMPAR(CP-AMPAR)是在神经元抑制过程中形成的，是表达动态平衡可塑性所必需的。然而，CP-AMPAR在体内平衡调节过程中生物发生的分子机制在很大程度上仍不清楚。我们发现，miR124是一种脑富集型microRNA(MiRNA)，通过靶向GluA2 mRNA的3‘-UTR抑制GluA2翻译，导致CP-AMPAR的形成。重要的是，我们发现抑制miR124功能可以取消无活性诱导的稳态调节。因此，我们假设，不活跃通过表观遗传修饰上调miR124的表达，导致GluA2翻译抑制和CP-AMPAR的形成，从而导致动态平衡突触可塑性的表达。在这项拟议的研究中，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及其辅助因子脱乙酰酶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转录复合体在动态平衡可塑性表达中的作用。这些研究将为我们理解神经功能动态平衡和网络稳定性提供新的线索。CP-AMPAR生物发生的阐明也将对临床研究产生影响，因为CP-AMPAR与中风、肌萎缩侧索硬化症和药物成瘾等疾病有关。

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.