Atypical astrocytes in the aging cortex

老化皮质中的非典型星形胶质细胞

基本信息

批准号：
10552699
负责人：
Chris G Dulla
金额：
$ 20.63万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10552699
关键词：
1 year old ARHGEF5 gene Age Age Months Age-associated memory impairment Aging Amino Acid Transporter Anatomy Animals Appearance Area Astrocytes Astrocytosis Automobile Driving Biological Assay Blood Vessels Brain Buffers CSPG4 gene Cells Data Development Distal Electrophysiology (science)Excitatory Amino Acid Transporter 1 Excitatory Amino Acids Fluorescent in Situ Hybridization Frequencies Funding GLAST Protein Genetic Transcription Glial Fibrillary Acidic Protein Global Change Glutamate Transporter Glutamates Hippocampus Homeostasis Image Immunohistochemistry Impaired cognition Impairment Individual Mediating Messenger RNA Modeling Morphology Myelin Basic Proteins Neurons Oligodendroglia Phenotype Play Potassium Prefrontal Cortex Prevalence Process Property Proteins Publishing Reporting Risk Rodent Role Shapes Somatosensory Cortex Synapses Synaptic Transmission Testing Work age related aged cognitive function executive function extracellular immunoreactivity inward rectifier potassium channel male nervous system disorder neural circuit neuropathology normal aging novel reconstruction single-cell RNA sequencing spatial memory timeline uptake voltage

项目摘要

SUMMARY. During normal aging, astrocytes change their transcriptional and functional properties. Astrocyte play a central role in shaping neuronal function through their expression of excitatory amino acid transporters (EAATs: GLT-1 and GLAST), which mediate glutamate uptake, and the inwardly rectifying K+ channel, Kir4.1, which buffers extracellular K+. While we know that EAAT and Kir4.1 expression are developmentally regulated, we know little about their role in normal aging. This proposal is built on our novel finding that progressively more astrocytes lose EAAT and Kir4.1 expression during aging. Surprisingly, this loss is not a gradual, global change but occurs on a cell-by-cell basis with individual astrocytes expressing minimal EAAT and Kir4.1, while neighboring astrocytes remain normal. These “atypical astrocytes” are found predominantly in the retrosplenial and prefrontal cortices (RSC and PFC), but not in the hippocampus or somatosensory cortex. Atypical astrocytes are more abundant in males, and grow in number as animals age. By  1 year of age, up to 15% of astrocytes are atypical in these regions. Interestingly, atypical astrocytes are not reactive, as they lack elevated GFAP immunoreactivity. Importantly, atypical astrocytes are Sox9 positive, showing that they are in fact astrocytes. They also do not label for NG2 (OPC marker), MBP (oligodendrocyte marker), or NeuN (neuronal marker). Atypical astrocytes are often associated with blood vessels, but whether vascular changes contribute to their emergence is unknown. Based on preliminary data, we hypothesize that atypical astrocytes accumulate in the RSC and PFC during normal aging and cause domains of impaired glutamate and K+ uptake. This is significant because these areas play a prominent role in spatial memory and executive function. If our hypothesis is correct, the loss of glutamate and K+ uptake could contribute to age-related losses in cognitive functions associated with these regions. In addition, the combined loss of EAATs and Kir4.1 during aging may be especially detrimental. We recently published that bursts of neuronal activity > 30 Hz drives synapse-specific inhibition of glutamate uptake. We suspect this is due to focal K+-mediated depolarization of astrocyte distal processes driving voltage-dependent inhibition of EAAT function. Using genetically encoded voltage indicators (GEVIs), our preliminary data shows that astrocyte distal processes undergo significant activity-induced depolarization, in line with voltage-dependent EAAT inhibition. Because Kir4.1 is critical to buffering extracellular K+, its loss in aging likely exacerbates activity-induced astrocyte depolarization and increases voltage-dependent suppression of glutamate uptake. Here, we will use electrophysiology, glutamate and GEVI imaging, and anatomical approaches to determine whether RSC and PFC astrocytes lose expression of EAATs and Kir4.1 during aging and whether this leads to disrupted glutamate uptake and K+ buffering. When completed, we will be poised to establish the mechanisms that induce atypical astrocytes and determine whether atypical astrocytes contribute to age-related synaptic and cognitive dysfunction.

概括。在正常衰老过程中，星形胶质细胞会改变其转录和功能特性。通过表达兴奋性氨基酸转运蛋白（EAAT：GLT-1）来塑造神经功能和 GLAST），介导谷氨酸吸收，内向整流 K+ 通道 Kir4.1，缓冲虽然我们知道 EAAT 和 Kir4.1 的表达受到发育调节，但我们知之甚少。关于它们在正常衰老中的作用这一提议是建立在我们的新发现之上的，该发现越来越多。令人惊讶的是，星形胶质细胞在衰老过程中失去了 EAAT 和 Kir4.1 的表达，这种损失并不是逐渐的、全面的。变化，但发生在逐个细胞的基础上，单个星形胶质细胞表达最少的 EAAT 和 Kir4.1，而邻近的星形胶质细胞保持正常。这些“非典型星形胶质细胞”主要存在于压后皮质和前额皮质（RSC 和 PFC），但不在海马或体感皮质中。非典型星形胶质细胞在雄性中更为丰富，并且随着动物年龄的增长，其数量会增加，直至年龄增长。 15% 的星形胶质细胞在这些区域是非典型的，非典型星形胶质细胞不具有反应性，因为它们。重要的是，非典型星形胶质细胞呈 Sox9 阳性，表明它们处于 GFAP 免疫反应性水平。事实上，它们也不标记 NG2（OPC 标记）、MBP（少突胶质细胞标记）或 NeuN（神经元标记）。非典型星形胶质细胞通常与血管相关，但血管变化是否有所贡献。根据初步数据，我们追踪非典型星形胶质细胞的出现。正常衰老期间在 RSC 和 PFC 中积累，导致谷氨酸和 K+ 域受损这很重要，因为这些区域在空间记忆和执行功能中发挥着重要作用。如果我们的假设正确，谷氨酸和 K+ 吸收的丧失可能会导致与年龄相关的认知能力下降此外，衰老过程中 EAAT 和 Kir4.1 的联合丢失可能会导致这些区域相关的功能。我们最近发表了> 30 Hz 的神经活动爆发会驱动突触特异性。我们怀疑这是由于星形胶质细胞远端局灶性 K+ 介导的去极化所致。使用基因编码的电压指示器驱动 EAAT 功能的电压依赖性抑制。（GEVI），我们的初步数据表明星形胶质细胞远端过程经历显着的活动诱导去极化，与电压依赖性 EAAT 抑制一致，因为 Kir4.1 对于缓冲细胞外至关重要。 K+，其衰老过程中的损失可能会加剧活动诱导的星形胶质细胞去极化并增加电压依赖性在这里，我们将使用电生理学、谷氨酸和 GEVI 成像，以及确定 RSC 和 PFC 星形胶质细胞是否失去 EAAT 和 Kir4.1 表达的解剖学方法老化过程中，这是否会导致谷氨酸吸收和 K+ 缓冲中断。完成后，我们将进行研究。准备建立诱导非典型星形胶质细胞的机制并确定非典型星形胶质细胞是否导致与年龄相关的突触和认知功能障碍。