The cytoskeleton in neuronal cell biology

神经细胞生物学中的细胞骨架

• 批准号: RGPIN-2016-03847
• 负责人: Nguyen, MinhDang
• 金额: $ 2.26万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=614667
• 关键词: cytoskeleton; neuronal; cell; biology

The cytoskeleton is an evolutionarily conserved structure consisting of an internal filamentous protein scaffold that controls the architectural and functional features of cells. Composed by the interconnection of microtubule filaments (MTs), actin microfilaments (MFs), intermediate filaments and their associated proteins, the cytoskeleton serves as a “highway” for intracellular transport, provides architectural support to cells and participates in cell signaling. It is particularly critical in neurons as it allows these cells to respond morphologically and functionally to depolarization. My application proposes to decipher the “structure -> function” relationship played by the cytoskeleton in neurons with a particular focus on the process of learning and memory. “Is the cytoskeleton important for learning and memory?”. “How does the cytoskeleton contribute to memory formation?” Dynamic changes underlying the maintenance of the connections (synapses) between nerve cells are thought to be responsible for the restructuring of neural networks that serve to encode behaviors including memories. Synapses are composed by a presynaptic side (i.e. axon terminal) and a post-synaptic side (i.e. spine protruding from a dendrite). Despite the fact that both sides are regulated by cytoskeleton, the role of the cytoskeleton in learning and memory is not well understood. My lab has recently generated a unique animal model that allows us to study the cytoskeleton-dependent postnatal mechanisms underlying spatial learning and memory. Our new animal model that was created by gene knockout of a particular cytoskeletal protein, develops normally. Importantly, the mutants exhibit profound spatial learning deficits 7 weeks after birth. Ultra-structural studies revealed early cytoskeletal abnormalities in dendrites of pyramidal excitatory neurons in the CA1 region of the hippocampus, a key brain area implicated in learning and memory. Genome-wide transcriptome profiling of hippocampi of the mutant animals revealed deregulation of cell adhesion and cytoskeletal genes involved in neuronal plasticity. Here, I propose 1) to determine whether deregulation of the cytoskeleton in pyramidal excitatory neurons affects the biology of neighbor inhibitory interneurons, as well as the interface between the two cell types, thereby altering the neural network, 2) to validate cell adhesion and cell-cell communications proteins identified from the transcriptome analysis that modulate the activity between these cell types and determine how it relates to the cytoskeleton in pyramidal neurons, and 3) to address the non-cell autonomous functions of cytoskeletal proteins, a topic that is not covered in the current literature. The experiments will allow us to understand how the cytoskeleton impacts cell-cell communication and preserve neuronal networks in the postnatal brain during learning and memory.

细胞骨架是一种进化上保守的结构，由控制细胞结构和功能的内部丝状蛋白支架组成。细胞骨架由微管微丝(MTS)、肌动蛋白微丝(MFS)、中间丝及其相关蛋白组成，是细胞内运输的“高速公路”，为细胞提供结构支持，参与细胞信号转导。它在神经元中尤其关键，因为它允许这些细胞在形态和功能上对去极化做出反应。我的申请书建议 为了破译“结构” -&gt；细胞骨架所扮演的“功能”关系 在神经元中特别关注学习和记忆的过程。“就是 细胞骨架对学习和记忆重要吗？““细胞骨架是如何 对记忆的形成有贡献吗？“维护基础的动态变化 神经细胞之间的连接(突触)被认为是 用于重组用于对行为进行编码的神经网络 包括回忆。突触由突触前侧(即轴突)组成 终末)和突触后侧(即突触从树突突起)。 尽管双方都受到细胞骨架的调节，但细胞骨架在学习和记忆中的作用还没有被很好地理解。 我的实验室最近产生了一种 独特的动物模型，使我们能够研究细胞骨架依赖 空间学习和记忆的后天机制。我们的新动物 通过基因敲除特定的细胞骨架蛋白而创建的模型， 发育正常。重要的是，突变体表现出深刻的空间学习能力。 出生后7周出现缺乏症。超结构研究很早就揭示了 大鼠锥体兴奋性神经元树突的细胞骨架异常 海马区的CA1区，一个关键的大脑区域，与学习和 记忆。突变动物海马区全基因组转录组谱分析 揭示了参与细胞黏附和细胞骨架基因的放松调控 神经元的可塑性。 在这里，我建议1)确定放松管制是否 锥体兴奋性神经元中细胞骨架的变化对生物学的影响 相邻抑制性中间神经元，以及 两种细胞类型之间的接口，从而改变神经网络，2) 验证已确定的细胞黏附和细胞间通讯蛋白 从调节这些细胞之间的活动的转录组分析 分类并确定它与锥体神经元细胞骨架的关系， 3)解决细胞骨架的非细胞自主功能 蛋白质，这是目前文献中没有涉及的一个主题。这些实验将使我们了解如何 细胞骨架影响细胞与细胞之间的通讯 在学习和记忆过程中保护出生后大脑中的神经元网络。