Molecular Mechanisms of Neurotransmitter Release

我们如何感知、移动、感觉、学习和记忆，都是神经细胞形成回路的能力的产物，这些回路允许我们以异常快速和精确的方式处理信息。信息通过称为突触的特殊细胞间接触点在细胞间传递。尽管取得了巨大的进步，但理解促进、维持和/或重新安排突触功能和/或结构的分子机制仍然是当代神经科学中的一个关键问题。利用遗传方法，我们发现了一种新的蛋白质（WD40A），它在果蝇和人类中非常相似。我们假设WD40A可能控制另一种未表征蛋白（ATP8B）的蛋白水平，该蛋白可能控制突触膜的脂质（即脂肪酸）组成，从而促进信息从一个神经细胞传递到另一个神经细胞。为了更好地支持这一假设，我们将利用电记录和光学记录来探讨WD40A在突触功能和结构中的作用和意义，以检验WD40A基因突变对突触功能的影响。此外，遗传和生化方法将被用来准确表征WD40A如何控制突触中的ATP8B蛋白水平。该项目将开发有价值的研究工具，这些工具将免费提供给研究界，并将为研究生和本科生提供研究机会。这项工作有望描述一种全新的分子机制，该机制诱导突触脂质环境的局部变化，帮助神经细胞之间的快速通信。这些知识将极大地推进我们对大脑如何能够在毫秒尺度上计算信息的理解，并提高我们设计更好的医疗方法来治疗或预防人类的一些神经系统疾病的能力。

How we perceive, move, feel, learn, and remember is a product of the ability of nerve cells to form circuits that allow an extraordinarily fast and precise communication processing information. Information is transferred from cell to cell through specialized cell-cell contact sites, termed synapses. Despite tremendous advances, understanding the molecular mechanisms facilitating, maintaining and/or re-arranging synaptic function and/or structure remains a key problem in contemporary neuroscience. Using a genetic approach, we identified a new protein (WD40A) that is very similar from fruit flies to humans. We hypothesize that WD40A may control the protein levels of another uncharacterized protein (ATP8B) that may control the lipid (i.e., fatty acid) composition of the synaptic membranes that facilitate information transfer from one nerve cell to another. To better support this hypothesis, the role and significance of WD40A for synaptic function and structure will be explored using electrical and optical recordings to examine the effects of genetic mutations in WD40A on synaptic function. In addition, genetic and biochemical approaches will be used to characterize exactly how WD40A controls ATP8B protein levels at synapses. The project will develop valuable research tools that will be made freely available to the research community and will provide research opportunities for both graduate and undergraduate students. This work is expected to characterize a fundamentally new molecular mechanism that induces local changes in the lipid environment of synapses aiding rapid communication among nerve cells. This knowledge will significantly advance our understanding of how the brain is able to compute information on a millisecond scale, and improve our ability to design better medical approaches to treat or prevent some neurological disorders in humans.