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: 10532682
• 负责人: Philip Henry Hwang
• 金额: $ 4.61万
• 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/10532682
• 关键词: 2 year old; Ablation; Address; Adenosine; Adult; Affect; Affinity Chromatography; Age; Aging; Agonist; Animals; Attenuated; Behavior; Brain; Brain region; Cells; Corpus striatum structure; Data; Development; Disease; Enzymes; Feedback; Functional disorder; Gene Expression; Gene Expression Profiling; Generations; Genes; Genetic; Glutamates; Goals; Human; Immediate-Early Genes; Impaired cognition; Inflammation; Inflammatory; Knock-out; Locomotion; Macrophage; Mediating; Metabolism; Microdialysis; Microglia; Modeling; Molecular; Motor Activity; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Pathway interactions; Play; Predisposition; Prevention; Production; Purinergic P1 Receptors; Regulation; Ribosomes; Role; Seizures; Specificity; Synapses; Transgenic Mice; Translating; age related; aged; aging brain; experimental study; extracellular; genetic approach; in vivo; insight; mouse model; neuronal circuitry; neuronal excitability; neuropathology; neuroprotection; neurotransmission; novel; novel strategies; pathogen; postsynaptic; postsynaptic neurons; presynaptic; receptor; response

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.

项目概要/摘要 该提案提出了一种新型小胶质细胞控制的神经元活动反馈机制及其潜力 对衰老依赖性神经病理学的贡献。小鼠和人类的衰老与以下基因的改变有关 神经元回路兴奋性和功能、癫痫易感性增加和神经变性。我们最近的 研究已确定小胶质细胞是神经元活动和功能的新型调节剂，可维持体内平衡 神经元激活水平，从而充当过度兴奋的刹车片。初步证据表明 这种神经保护功能可能会随着衰老而改变，这可能是炎症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。我假设小胶质细胞发挥着关键作用 衰老大脑中的异常神经元反应和功能障碍。为了支持这个想法，我们发现小胶质细胞 能够通过响应过程中释放的 ATP 以活动依赖性方式调节神经元活动 神经元激活并将其代谢为腺苷，从而抑制神经元活动。我们进一步发现 小胶质细胞中促炎基因表达与年龄相关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，使用健康成人纹状体作为模型。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， 在小胶质细胞中表达，但也在纹状体 D2 中型多棘神经元中表达。这表明小胶质细胞可能 通过表达 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-神经元相互作用。为了研究这一点，我们建议生成转基因小鼠模型 确定小胶质细胞与 D2 中型多棘神经元上发现的 CD73 的相对贡献。小胶质细胞 腺苷产生的充足性可能表明这是一种全脑神经保护机制 异常的神经元激活。此外，为了研究这种现象的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 中型多刺神经元。预防基于腺苷的神经元活性抑制 突触前或突触后将重现小胶质细胞腺苷生成丧失所见的影响。使用 在这些模型中，我们将通过立即早期基因表达、开放场运动来评估神经元激活 活动和癫痫易感性。我们进一步证明了参与小胶质细胞的关键基因的表达 驱动的神经元活动调节在老年动物中下调。不过这还有待具体 在小胶质细胞中观察到。因此，我们建议专门针对小胶质细胞进行基因表达分析 不同的大脑区域和不同年龄的动物。这些信息对于我们了解细胞至关重要 小胶质细胞调节神经元功能的机制，可能有助于识别其关键调节因子 途径，导致开发治疗与年龄相关的疾病的新方法。