Age-dependent effects on microglia-mediated control of neuronal activity

小胶质细胞介导的神经元活动控制的年龄依赖性影响

• 批准号: 10314367
• 负责人: Philip Henry Hwang
• 金额: $ 4.44万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10314367
• 关键词: Age; dependent; effects; microglia; mediated

Project Summary/Abstract This proposal addresses a novel microglia-controlled neuronal activity feedback mechanism and its potential contribution to aging-dependent neuropathology. Aging in mice and humans is associated with alterations to neuronal circuit excitability and function, increased seizure susceptibility, and neurodegeneration. Our recent studies have identified microglia as novel regulators of neuronal activity and function, maintaining homeostatic levels of neuronal activation, thereby serving as brake pads for hyperexcitation. Preliminary evidence suggests this neuroprotective function may be altered in aging, potentially as a consequence of inflammatory microglia activation associated with aging and neurodegenerative disease. I hypothesize that microglia play a critical role in aberrant neuronal responses and dysfunction in the aging brain. In support of this idea, we found that microglia are able to regulate neuronal activity in an activity dependent manner by responding to ATP released during neuronal activation and metabolizing it into adenosine, thereby suppressing neuronal activity. We further found that age-associated increase in pro-inflammatory gene expression in microglia is associated with changes in this mechanism. To investigate my hypothesis, I will first elucidate the exact mechanisms of microglia-mediated neurosuppression, using the healthy adult striatum as a model. Microglia express the rate-limiting enzyme, CD39, which controls ATP to AMP degradation, while AMP to adenosine degradation is accomplished by CD73, which is expressed in microglia but also by striatal D2 medium spiny neurons. This suggests that microglia may either be independently sufficient to produce adenosine by expressing both CD39 and CD73, or this mechanism requires microglia-neuron interactions. To investigate this, we propose to generate transgenic mouse models to identify the relative contributions of CD73 found on microglia versus D2 medium spiny neurons. Microglial sufficiency of adenosine production may implicate this as a brain-wide mechanism of neuroprotection against aberrant neuronal activation. Additionally, to investigate the presynaptic and postsynaptic specificity of this microglial mechanism, we will use transgenic mouse models lacking adenosine receptor either on projection neurons or D1 medium spiny neurons. Prevention of adenosine-based neuronal activity inhibition on either the presynapse or postsynapse will recapitulate the effects seen with loss of microglial adenosine generation. Using these models, we will assess neuronal activation by immediate early gene expression, open field locomotor activity, and seizure susceptibility. We further demonstrated that expression of key genes involved in microglia driven neuronal activity modulation are downregulated in aged animals. However, this has yet to be specifically observed in microglia. Therefore, we proposed to perform gene expression analysis specifically in microglia of different brain regions and animals of different ages. This information is critical to our understanding of the cellular mechanisms by which microglia regulate neuronal function and may help to identify key regulators of this pathway, leading to the development of novel approaches for the treatment of age-associated disorders.

项目摘要/摘要 该提案解决了一种新型的小胶质细胞控制的神经元活动反馈机制及其潜力 对依赖衰老的神经病理学的贡献。小鼠和人类的衰老与变化有关 神经元回路的兴奋性和功能，癫痫发作易感性增加和神经退行性。我们最近 研究已将小胶质细胞确定为神经元活性和功能的新调节剂，维持体内平衡 神经元激活的水平，从而充当过度刺激的制动垫。初步证据表明 这种神经保护功能可能在衰老中改变，这可能是由于炎症性小胶质细胞的结果 与衰老和神经退行性疾病有关的激活。我假设小胶质细胞起着至关重要的作用 在异常的神经元反应和衰老大脑的功能障碍中。为了支持这个想法，我们发现小胶质细胞 能够通过响应在 神经元激活并将其代谢成腺苷，从而抑制神经元活性。我们进一步发现 小胶质细胞中与年龄相关的促炎基因表达的增加与这种变化有关 机制。为了研究我的假设，我将首先阐明小胶质细胞介导的确切机制 神经抑制，使用健康的成年纹状体作为模型。小胶质细胞表达限速酶CD39， 控制ATP的ATP降解，而AMP到腺苷降解是由CD73完成的，这是 在小胶质细胞和纹状体D2培养基神经元中表达。这表明小胶质细胞可能 通过表达CD39和CD73或该机制独立地产生腺苷 需要小胶质细胞 - 神经元相互作用。为了调查这一点，我们建议将转基因小鼠模型生成 确定在小胶质细胞与D2培养基神经元中发现的CD73的相对贡献。小胶质细胞 腺苷产生的充分性可能将其视为神经保护的脑部机制 异常的神经元激活。此外，要研究此突触前和突触后特异性 小胶质细胞机制，我们将使用缺乏腺苷受体的转基因小鼠模型进行投影 神经元或D1中棘神经元。预防基于腺苷的神经元活性抑制任一 偶然的或自节后会概括损失小胶质细胞腺苷产生的作用。使用 这些模型，我们将通过立即的早期基因表达评估神经元激活 活动和癫痫发作的敏感性。我们进一步证明了与小胶质细胞有关的关键基因的表达 老年动物中驱动的神经元活性调节被下调。但是，这尚未具体 在小胶质细胞中观察到。因此，我们提出了在小胶质细胞中专门进行基因表达分析 不同年龄的不同大脑区域和动物。这些信息对于我们对细胞的理解至关重要 小胶质细胞调节神经元功能并有助于确定关键调节剂的机制 途径，导致开发与年龄相关疾病的新方法。