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 这项建议提出了一种新的小胶质细胞控制的神经元活动反馈机制及其潜力 对衰老依赖神经病理学的贡献。小鼠和人类的衰老与 神经元回路兴奋性和功能，癫痫敏感性增加，以及神经变性。我们最近 研究发现，小胶质细胞是神经元活动和功能的新调节器，维持内环境平衡。 神经元的激活水平，从而充当过度兴奋的刹车片。初步证据表明 这种神经保护功能在衰老过程中可能会改变，可能是炎性小胶质细胞的结果。 与衰老和神经退行性疾病相关的激活。我假设小胶质细胞起着关键作用。 在老化的大脑中异常的神经元反应和功能障碍。为了支持这一观点，我们发现小胶质细胞 能够通过对过程中释放的ATP做出反应，以一种活动依赖的方式调节神经元的活动 神经元激活并将其代谢成腺苷，从而抑制神经元的活动。我们进一步发现 与年龄相关的小胶质细胞促炎基因表达的增加与这一变化有关 机制。为了验证我的假设，我将首先阐明小胶质细胞介导的确切机制。 神经抑制，以健康成年纹状体为模型。小胶质细胞表达限速酶CD39， 它控制ATP到AMP的降解，而AMP到腺苷的降解是由CD73完成的，CD73 在小胶质细胞中表达，也在纹状体D2中棘神经元表达。这表明小胶质细胞可能是 通过同时表达CD39和CD73独立地足以产生腺苷，或者这种机制 需要小胶质细胞与神经元的相互作用。为了研究这一点，我们建议产生转基因小鼠模型来 确定在小胶质细胞上发现的CD73相对于D2中等刺神经元的相对贡献。小胶质细胞 腺苷产生的充分性可能暗示这是一种全脑的神经保护机制 异常的神经元激活。此外，为了研究突触前和突触后的特异性， 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D_1中棘神经元。以腺苷为基础的神经元活动抑制在以下两个方面的预防 突触前或突触后将重现失去小胶质细胞腺苷生成的影响。vbl.使用 在这些模型中，我们将通过即刻早期基因表达、旷场运动来评估神经元的激活 活动性和癫痫敏感度。我们进一步证明了与小胶质细胞有关的关键基因的表达 被驱动的神经元活动调节在老年动物中下调。然而，这还没有具体到 在小胶质细胞中观察到。因此，我们提出在小胶质细胞中特异性地进行基因表达分析。 不同的大脑区域和不同年龄的动物。这些信息对于我们理解细胞 小胶质细胞调节神经元功能的机制，并可能有助于确定其关键调节因子 这一途径导致了治疗年龄相关疾病的新方法的发展。