Regulation of Arp2/3-mediated actin polymerisation by PICK1 in neuronal function

大脑中的神经细胞（神经元）通过称为突触的连接相互交流。一种化学物质（神经递质）从一个神经元释放出来，并通过突触激活相邻神经元的受体。突触可以通过改变突触中神经元表面的受体数量来改变其强度（称为“突触可塑性”）。这个过程被认为是学习和记忆的基础，因为记忆很可能存储在相互连接的神经元回路中。在神经元周围移动受体的一个重要机制涉及到一种叫做肌动蛋白的蛋白质，这种蛋白质形成的细丝可以收缩和生长，从而在物理上操纵细胞的某些部分或其成分。我们发现一种蛋白质（称为PICK1）参与控制这些肌动蛋白丝的形成，并以这种方式控制神经递质受体进出突触的运动。单个神经元是控制复杂行为或记忆系统的神经元回路的组成部分，这些神经元接收触发其内部生化反应的各种输入。这些生化反应可以影响细胞中无数不同的过程，我们提出PICK1对肌动蛋白的调节可以通过这种方式控制。因此，在拟议的研究中，我们的目标是研究PICK1如何“打开”或“关闭”其对肌动蛋白丝的控制。在这项工作中，我们将研究三种类型的生化反应，它们都是众所周知的细胞机制的特定品种。我们将首先在试管中进行蛋白质分子实验，研究生化过程，然后在体外培养的活神经元上进行实验，研究操纵这些生化反应如何影响突触可塑性。我们将使用两种方法来研究神经元的突触可塑性。首先，我们将使用显微镜可视化神经递质受体的运动，其次，我们将通过记录神经元的电活动来分析神经元的活动。这项工作很重要，因为它将导致大量关于突触可塑性的新信息，从而导致学习和记忆机制。神经递质受体进出突触的运动被认为是一些脑部疾病（如中风、阿尔茨海默氏症和药物成瘾）中神经元活动改变的基础。因此，我们将在这项研究中研究的机制将增加我们对这些使人衰弱的疾病的认识，并可能有助于开发治疗方法。此外，肌动蛋白的控制对我们身体中所有细胞的许多过程都是绝对必要的，而不仅仅是神经元。因此，这项工作将提供重要的信息，将加强许多其他细胞过程和疾病机制的研究。

Nerve cells (neurons) in the brain communicate with one another at connections called synapses. A chemical (neurotransmitter) is released from a neuron and travels across the synapse to activate receptors in the adjacent neuron. Synapses can change their strength (known as 'synaptic plasticity') by altering the number of receptors found on the surface of the neuron in the synapse. This process is thought to underlie learning and memory, because the memory is likely to be stored in a circuit of interconnected neurons. An important mechanism for moving receptors around neurons involves a protein called actin, which forms filaments that shrink and grow to physically manoeuvre parts of the cell or its constituents. We have found that a protein (called PICK1) is involved in controlling the formation of these actin filaments, and in this way controls the movement of neurotransmitter receptors to or from the synapse. Individual neurons are constituents of neuronal circuits that control complex behaviour or memory systems, and these neurons receive various inputs that trigger biochemical reactions inside them. These biochemical reactions can influence countless different processes in cells, and we propose that PICK1's regulation of actin could be controlled in this way. Therefore, in the proposed research, we aim to investigate how PICK1 is 'switched on' or 'switched off' with respect to its control of actin filaments. We are going to investigate three types of biochemical reaction in this work, all of which are specific varieties of well-known cellular mechanisms. We will initially carry out experiments on protein molecules in test-tubes to study the biochemical processes, and then do experiments in living neurons cultured in vitro to investigate how manipulating these biochemical reactions affects synaptic plasticity. We will use two approaches to study synaptic plasticity in neurons. First, we will visualise the movement of neurotransmitter receptors using microscopy, and second, we will analyse the activity of neurons by recording their electrical activity. This work is important because it will lead to a wealth of new information about synaptic plasticity, and hence learning and memory mechanisms. The movement of neurotransmitter receptors to and from the synapse is thought to underlie the altered neuronal activity in several brain diseases, such as stroke, Alzheimer's, and also in drug addiction. Therefore, the mechanisms that we will study in this research will add to our knowledge about these debilitating diseases, and may contribute to developing therapies. In addition, the control of actin is absolutely essential to numerous processes in all of the cells in our bodies, not just neurons. Therefore, this work will provide important information that will enhance the study of many other cellular processes and disease mechanisms.