Voltage Imaging of Astrocyte-Neuron Interactions

星形胶质细胞-神经元相互作用的电压成像

基本信息

批准号：
10711423
负责人：
Chris G Dulla
金额：
$ 41.25万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10711423
关键词：
Acceleration Action Potentials Affect Age Months Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease therapy Amino Acid Transporter Anatomy Astrocytes Astrocytosis Binding Blood - brain barrier anatomy Brain Cessation of life Clinical Data Development Disease Disease Progression Excitatory Amino Acid Antagonists Excitatory Amino Acids Extracellular Space Functional disorder GLAST Protein Glutamates Heterozygote Hippocampus Homeostasis Human Image Mediating Memantine Metabolic Modeling Mus Neurons Optics Parents Pathologic Pathology Peripheral Phenotype Play Population Positioning Attribute Potassium Potassium Channel Process Proteins Role Seizures Shapes Specificity Synapses Testing Time aged disease phenotype early onset excitotoxicity experience extracellular glutamatergic signaling mouse model neuroinflammation neurotransmission normal aging overexpression prevent response uptake voltage

项目摘要

ABSTRACT. Astrocytes control neurotransmission, contribute to a robust blood-brain-barrier (BBB), and metabolically support neuronal activity. In Alzheimer’s Disease (AD), astrocytes become reactive near A plaques, contribute to neuroinflammation, and contribute to synaptic and circuit abnormalities. The role that astrocytes play in controlling synaptic excitation by removing glutamate from the extracellular space is particularly intriguing in AD. Astrocytes express high levels of excitatory amino acid transporters (EAATs), including GLT1 and GLAST, in their peripheral processes that bind and remove extracellular glutamate to limit synaptic excitation. EAATs, as well as other astrocyte proteins, are known to be decreased late in AD progression. Aberrant glutamate signaling is thought to contribute to AD progression, as evidenced by the clinical use of memantine, a glutamate receptor antagonist, as an AD therapy, strongly implicating EAATs in the progression of AD. Finally, soluble A inhibits EAAT function during heightened neuronal activity. Interestingly, we recently showed that neuronal activity causes astrocyte depolarization, which drives voltage-dependent inhibition of EAAT function to enhance neuronal activation. In the parent R01, we use astrocyte-expressed genetically encoded voltage indicators (GEVIs) to optically quantify Vm and showed that neuronal activity depolarizes peripheral astrocyte processes (PAPs) with synapse-specificity. In this supplement request, we provide preliminary data that during normal aging astrocytes sporadically lose the expression of GLT1, GLAST, and Kir4.1 and take on a phenotype known as atypical astrocytes (AtAs). Importantly, AtAs are not a form of reactive astrocytosis. Preliminary data suggests AtAs are more abundant and occur earlier in the APPNL-G-F mouse model of AD and are seen in the aged human brain. Here we will test they hypothesis that because AtAs, which lack Kir4.1 and GLT-1, are abundant in the hippocampus of APPNL-G-F mice, astrocytes experience increased activity-induced depolarization, leading to exaggerated inhibition of glutamate uptake. This creates a situation in which increased neuronal activity could drive synergistic voltage-dependent and A-mediated EAAT inhibition in AD. We chose to use the APPNL-G-F model due to its early onset, overlapping with the normal development of AtAs, without APP overexpression. Using the APPNL-G-F mice, we will determine: (SA1) “Do hippocampal astrocytes in APPNL-G-F mice show increased Vm responses to neuronal activity?” and (SA2) “Is activity-dependent inhibition of glutamate uptake enhanced in the hippocampus of APPNL-G-F mice?“. Both increased activity-induced PAP depolarization and elevated A could alter activity-induced EAAT inhibition in APPNL-G-F mice. If so, this would position astrocyte-neuron interactions, K+ and glutamate homeostasis as key players in early AD progression and would motivate enhancing glutamate and K+ uptake to reduce AD-related pathology. When complete, we will know whether newly discovered changes in PAP Vm are exaggerated and contribute to aberrant glutamate excitation in APPNL-G-F mice. We will be poised to leverage these findings to enhance K+ and glutamate homeostasis to prevent pathological excitation in AD.

抽象的。星形胶质细胞控制神经传递，有助于建立强大的血脑屏障 (BBB)，并提供代谢支持在阿尔茨海默病 (AD) 中，星形胶质细胞在 A 斑块附近变得活跃，有助于神经炎症，并导致突触和回路异常，星形胶质细胞在其中发挥的作用。通过从细胞外空间去除谷氨酸来控制突触兴奋在 AD 中尤其令人感兴趣。星形胶质细胞表达高水平的兴奋性氨基酸转运蛋白 (EAAT)，包括 GLT1 和 GLAST，它们的外周过程结合并去除细胞外谷氨酸以限制突触兴奋。以及其他星形胶质细胞蛋白，已知在 AD 进展后期谷氨酸信号异常会减少。谷氨酸受体美金刚的临床使用证明，被认为会导致 AD 进展拮抗剂作为 AD 疗法，与 EAAT 密切相关。最后，可溶性 A 抑制。 EAAT 在呼吸神经元活动期间发挥作用。引起星形胶质细胞去极化，从而驱动 EAAT 功能的电压依赖性抑制，以增强在亲本 R01 中，我们使用星形胶质细胞表达的基因编码电压指示器。（GEVI）光学量化 Vm 并表明神经元活动使外周星形胶质细胞过程去极化（PAP）具有突触特异性。在此补充请求中，我们提供了正常衰老过程中的初步数据。星形胶质细胞偶尔会失去 GLT1、GLAST 和 Kir4.1 的表达，并呈现出称为重要的是，初步数据表明，AtAs 不是反应性星形细胞增多症的一种形式。 AtAs 在 AD 的 APPNL-G-F 小鼠模型中更丰富且出现更早，并且在老年人中也可见到在这里，我们将测试他们的假设，因为缺乏 Kir4.1 和 GLT-1 的 AtAs 在大脑中含量丰富。 APPNL-G-F 小鼠海马中，星形胶质细胞经历活动诱导的去极化增加，导致谷氨酸摄取的过度抑制会造成神经活动增加的情况。在 AD 中驱动协同电压依赖性和 A 介导的 EAAT 抑制。该模型由于其发病较早，与AtAs的正常发育重叠，没有APP过度表达。使用 APPNL-G-F 小鼠，我们将确定：（SA1）“APPNL-G-F 小鼠的海马星形胶质细胞是否表现出增加” Vm 对神经元活动的反应？”和（SA2）“活动依赖性谷氨酸摄取抑制是否增强 APPNL-G-F 小鼠的海马？“。活动诱导的 PAP 去极化的增加和 A 的升高都可以改变 APPNL-G-F 小鼠中活性诱导的 EAAT 抑制如果是这样，这将定位星形胶质细胞-神经元相互作用， K+ 和谷氨酸稳态是 AD 早期进展的关键因素，并会促进谷氨酸的增强完成后，我们将知道是否有新发现的变化。 PAP Vm 中的值被夸大并导致 APPNL-G-F 小鼠的谷氨酸兴奋异常。利用这些发现来增强 K+ 和谷氨酸稳态，以防止 AD 中的病理兴奋。