Circuit-based mechanisms of neuronal vulnerability in the adult EC

成人内皮细胞神经元脆弱性的基于回路的机制

• 批准号: 10400031
• 负责人: Caleb Wood
• 金额: $ 4.68万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2024-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400031
• 关键词: Action Potentials; Address; Adult; Alzheimer' s Disease; Apoptosis; Apoptotic; Automobile Driving; Axon; Binding; Brain; Brain region; Cell Death; Cells; Cessation of life; Chloride Channels; Chronic; Code; Cognitive deficits; Communication; Cytoplasmic Granules; Data; Development; Developmental Process; Disease; Electrophysiology (science); Engineering; Excision; Exhibits; Fire - disasters; Functional disorder; Future; Generations; Genetic; Gliosis; Glutamates; Glycine; Goals; Hippocampus (Brain); Infusion procedures; Injury; Ivermectin; Life; Ligands; Mediating; Memory; Modeling; Morphologic artifacts; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotransmitters; Pathway interactions; Pattern; Perforant Pathway; Pharmacology; Population; Process; Signal Transduction; Sodium Channel; Symptoms; Synapses; Synaptic plasticity; Testing; Tetanus Toxin; Tetrodotoxin; base; competitive environment; critical period; dentate gyrus; entorhinal cortex; experimental study; genetic approach; granule cell; in vivo; insight; mouse model; neuron loss; neuronal survival; neurotransmitter release; postnatal; postnatal development; postnatal period; postsynaptic; prevent; pro-apoptotic protein; response; way finding

Project summary/abstract. Entorhinal cortex layer II (ECII) neurons are some of the first cells to degenerate in Alzheimer’s Disease (AD). ECII axons form the perforant pathway and are the major cortical input into the hippocampus. The perforant pathway supports memory formation and spatial navigation throughout life, and loss of this input is consistent with the cognitive deficits that present early in AD. To mimic the loss of this input in AD, the Jankowsky lab created a chemogenetic mouse model of perforant pathway disruption in which a subset of ECII neurons express an engineered chloride channel (GlyCl) to prevent the generation of action potentials. We unexpectedly discovered that entorhinal neurons were highly vulnerable to silencing. Shortly after being inactivated, many ECII neurons retract their axons from the dentate gyrus, express pro- apoptotic proteins, and then are eliminated from the circuit. We observed similar neurodegeneration after eliminating neurotransmitter release with tetanus toxin (TeTX), confirming that neuronal loss is not an artifact of GlyCl activation. Further, this silencing-induced degeneration is not shared by other brain regions, as neither the pre/parasubiculum nor retrosplenial cortex exhibit cell loss after neuronal inactivation. This suggests that specific features of the entorhinal cortex may confer neuronal vulnerability to inactivity. One possible vulnerability could be related to the formation of entorhinal-hippocampal circuit. We noted that the pattern of ECII degeneration after silencing was strikingly similar to the processes that guide to refinement of the perforant pathway during development. In early post-natal periods, inactive ECII neurons are pruned from the circuit in a process that is mediated by local differences in activity, referred to as activity- dependent competition. Projections are only pruned when neurons are sparsely inactive - when all cells are equally inactive, none are removed. This proposal will test two hypotheses about the cellular mechanism driving neuronal death in the mature entorhinal cortex. Aim 1 will determine whether activity-dependent competition persists in the adult ECII. Pharmacological and genetic approaches will be used to modulate relative activity levels to determine how cell death is influenced by activity differences between neighboring cells. Aim 2 will determine whether post-synaptic partners promote the survival of ECII neurons. Our preliminary data suggests that eliminating neurotransmitter release from ECII neurons – without blocking action potentials - is sufficient to induce degeneration. I will therefore use pharmacological and genetic approaches to both reduce neurotransmitter binding in dentate granule cells and eliminate their ability to fire action potentials in response to ECII input. This will test whether neurotransmitter-mediate signaling, or post-synaptic activity itself, is required for ECII neuron survival. Data from these aims will determine how activity disruption may mediate cell death in the adult brain. Further, these data may suggest that mechanisms which drive cell death during postnatal development are not necessarily limited to critical periods but may persist into adulthood within certain pathways. Understanding these mechanisms may inform future studies on neurodegenerative disease and how circuit disruption may contribute to neuronal loss.

项目摘要/摘要。 II（ECII）神经元的内嗅皮层是第一个在阿尔茨海默氏病（AD）中退化的细胞。 ECII 轴突形成穿孔途径，是海马的主要皮质输入。穿孔道路支撑 记忆形成和空间导航一生，并且输入的丢失与认知缺陷一致 在广告中的早期。为了模仿AD中此输入的丢失，Jankowsky实验室创建了化学遗传小鼠模型 经济型途径中断，其中一部分ECII神经元将工程氯化物通道（Glycl）表达为 防止产生动作电位。我们出乎意料地发现，内嗅神经元非常容易受到伤害 沉默。失活后不久，许多ECII神经元从齿状回缩回轴突 凋亡蛋白，然后从电路中消除。我们观察到了相似的神经变性 神经递质用破伤风毒素（TETX）释放，确认神经损失不是Glycl激活的伪像。 此外，这种沉默引起的变性并不是其他大脑区域共享的 脾后皮质在神经元失活后表现出细胞丧失。这表明内嗅的特定特征 皮层可能赋予神经元脆弱性。一个可能的漏洞可能与形成有关 内嗅 - 海马电路。我们注意到沉默后的ECII变性模式与 在开发过程中穿孔途径改进的过程。在产后早期，不活跃的ECII 神经元是通过在活动局部差异介导的过程中从电路中修剪的，被称为活动 - 依赖竞争。只有在神经元稀疏活性时，预测才会修剪 - 当所有细胞均等时 无活性，没有删除。该提案将检验两个关于驱动神经元死亡的细胞机制的假设 成熟的内嗅皮层。 AIM 1将确定成人ECII中是否依赖活动竞争持续存在。 药理和遗传方法将用于调节相对活性水平以确定细胞死亡的方式 受邻近细胞之间的活性差异的影响。 AIM 2将确定后突触的伴侣是否 促进ECII神经元的生存。我们的初步数据表明，消除了从ECII释放神经递质 神经元 - 没有阻断动作电位 - 足以诱导退化。因此，我将使用药品 以及减少牙齿颗粒细胞中神经递质结合的遗传方法并消除了它们的射击能力 响应ECII输入的动作电位。这将测试神经递质 - 介质信号传导还是突触后的信号 活动本身是ECII神经元存活所必需的。来自这些目标的数据将决定活动中断如何 介导成人大脑的细胞死亡。此外，这些数据可能表明在驱动细胞死亡的机制 产后发展不一定仅限于关键时期，但可能会持续到成年 途径。了解这些机制可能会为关于神经退行性疾病的未来研究以及电路如何 破坏可能导致神经元丧失。