Molecular mechanisms of homeostatic synaptic plasticity

项目摘要 当受到外部或内部的干扰时，神经元能够恢复其活动。这种形式的 在发育和发育过程中，动态平衡反应对于维持神经元或网络的稳定性至关重要 大脑功能正常。在稳态突触可塑性(HSP)过程中，神经元活动的慢性抑制 导致突触定位的AMPA受体(AMPAR)代偿性增加和 突触电流。在基本条件下，AMPAR以含有GluA2的异构体形式存在，主要存在于 GluA1/GluA2或GluA2/GluA3形式。含有GluA2的AMPAR对钠是渗透性的，但 不透钙的对钙的抗性来自于一种独特的转录后修饰 GluA2基因的表达。腺苷脱氨酶ADAR2将腺苷编辑为肌苷 GluA2中的谷氨酰胺(Q)到精氨酸(R)，这使AMPAR具有钙不通透性。因此，效率低下 编辑GluA2 mRNA或在AMPAR通道复合体中缺乏GluA2的掺入将导致 钙透性AMPAR(CP-AMPAR)。虽然CP-AMPAR的作用已经被很好地认识到 热休克蛋白中的关键信号分子，关于CP生物发生的分子性质和机制。 热休克蛋白中的Ampar在很大程度上仍不清楚。我们假设在热休克期间，神经元的不活动会触发 细胞对ADAR2酶的位置和活性的反应，导致未编辑的GluA2和 含GluA2(Q)的CP-AMPAR的形成。此外，CP-AMPAR钙的分子底物 参与动态平衡反应的级联反应尚不清楚。我们假设CP-AMPAR 活性导致GluA1乙酰化，从而使AMPAR突触积累，导致表达 动态平衡可塑性。在这项提案中，我们的目标是研究调控背后的分子细节 GluA2编辑对CP-AMPAR的生物发生以及随后对AMPAR的修饰 乙酰化及其对体外动态平衡突触可塑性表达的影响 神经元和活体小鼠的视皮层。

Project Summary Neurons are able to restore their activity when challenged by external or internal perturbations. This form of homeostatic response is crucial for the maintenance of neuronal or network stability during development and normal brain function. During homeostatic synaptic plasticity (HSP), chronic suppression of neuronal activity leads to a compensatory increase in synaptically localized AMPA receptors (AMPARs) and the intensity of synaptic currents. Under basal conditions, AMPARs exist as GluA2-containing heterotetramers, mostly in the form of GluA1/GluA2 or GluA2/GluA3. The GluA2-containing AMPARs are permeable to sodium but impermeable to calcium. The resistance to calcium derives from a unique posttranscriptional modification of GluA2 mRNA. Editing of adenosine to inosine by the adenosine deaminase enzyme ADAR2 switches a glutamine (Q) to arginine (R) in GluA2, which confers calcium impermeability in AMPARs. Thus, inefficient editing of GluA2 mRNA, or a lack of incorporation of GluA2 in an AMPAR channel complex, will lead to calcium-permeable AMPARs (Cp-AMPARs). While the role for the Cp-AMPAR has been well recognized as a key signaling molecule in HSP, the molecular nature and mechanisms regarding the biogenesis of the Cp- AMPAR in HSP remains largely unknown. We hypothesize that during HSP, neuronal inactivity triggers cellular responses in the location and activity of the ADAR2 enzyme, leading to unedited GluA2 and the formation of GluA2(Q)-containing Cp-AMPARs. Also, the molecular substrates of the Cp-AMPAR calcium cascade that are involved in homeostatic responses remain unknown. We hypothesize that Cp-AMPAR activity leads to GluA1 acetylation which enables AMPAR synaptic accumulation, leading to the expression of homeostatic plasticity. In this proposal, we aim to examine the molecular details underlying the regulation of GluA2 editing for the biogenesis of Cp-AMPARs, as well as the subsequent modification of AMPARs by acetylation and their contribution to the expression of homeostatic synaptic plasticity in vitro in primary neurons and in vivo in the mouse visual cortex.