Synaptic and circuit pathology in a mouse model of AP4 deficiency syndrome

神经细胞（神经元）对大脑功能至关重要，当它们出错时，就会导致神经系统疾病。它们功能的关键是神经细胞的特殊形状，包括一个大的树突树，接收来自其他神经元的连接，以及一个细长的轴突过程，可以连接下游神经元。神经细胞可以通过一种叫做突触的特殊的细胞间接触点相互交流，在那里它们释放和检测神经递质。轴突和树突的正确形成是突触连接和正确运作的关键步骤。突触可以根据神经活动的变化而改变其强度，神经活动是认知、学习和记忆等关键大脑功能的重要属性。此外，如果突触在发育过程中没有正确连接（例如，轴突和树突没有正确形成），或者突触在以后的生活中出现问题，这可能会导致毁灭性的疾病，包括智力残疾和癫痫，以及精神分裂症和自闭症等神经精神疾病，以及阿尔茨海默病等神经退行性疾病。细胞包含一系列脂质膜结合的“细胞器”区室，它们在细胞内离散位置的重要过程区室化中起关键作用。蛋白质、膜和其他细胞成分通常需要在不同的细胞器室之间运输，这通常是通过膜运输或“货物运输”过程在称为囊泡的运输载体中进行的。通过控制神经元表面信号受体的水平，因此神经元信号泡运输对于大脑发育过程中的关键步骤以及突触连接的操作都是重要的。一个关键的受体家族是神经递质受体（大脑中的化学信号分子），它们被运送到囊泡中需要它们的地方，并在结合突触释放的GABA和谷氨酸等神经递质方面起着特殊的作用。本提案的一个关键目标是研究如何在不同细胞器之间进行货物递送的调节，表征蛋白质AP4的分子特性，我们认为AP4对于调节细胞器网络的稳态和受体信号的调节至关重要。当人类的AP4复合体出现问题时，就会导致毁灭性的神经系统疾病，除了痉挛性截瘫和步态问题外，还会导致智力残疾、大脑结构改变、癫痫。然而，我们仍然不知道AP4复合物功能障碍是如何导致这种毁灭性疾病的。我们特别想知道AP4复合物如何帮助脑细胞调节膜传递，以及脑细胞质膜中关键膜蛋白（如神经递质受体）的数量、活性和位置，以控制神经元信号。研究这些调控过程背后的分子机制将使我们更好地了解大脑在健康条件下是如何工作的。此外，由于货物运输中断与许多神经退行性疾病和神经精神疾病有关，我们提出的工作也可能导致对膜运输和突触功能改变的疾病的更好理解，如癫痫、中风、阿尔茨海默病、运动神经元疾病、亨廷顿病、精神分裂症和自闭症。

Nerve cells (neurons) are critical for brain function and when they go wrong this leads to neurological diseases. Key to their function is the nerve cells specialised shape which includes a large dendritic tree which receives connections from other neurons and a long thin axonal process which can connect to downstream neurons. Nerve cells can communicate with each other via specialised cell-cell contact sites called synapses where they release and detect neurotransmitters. The correct formation of axons and dendrites is a critical step that allows synapses to wire up and operate correctly. Synapses can change their strength in response to changes in neural activity, an important property for key brain functions such as cognition and learning and memory. Moreover if synapses do not wire correctly during development (for example because axons and dendrites don't properly form) or if the synapses go wrong later in life this can lead to devastating diseases including intellectual disability and epilepsy in addition to neuropsychiatric disorders like Schizophrenia and autism and neurodegenerative disorders like Alzheimer's diseases.Cells contain a series of lipid membrane bound 'organelle' compartments that play a key role in compartmentalising important processes at discrete locations within cell. Proteins, membrane and other cell constituents often need to be transported between different organelle compartments which is often carried out in transport carriers called vesicles by a process of membrane trafficking or 'cargo delivery'. By controlling the levels of signalling receptors on the neuronal surface and hence neuronal signalling vesicular trafficking is important for key steps during the developmental wiring up of the brain and then the operation of the synaptic connections. One key family of receptors that are transported to where they are needed in vesicles are the receptors for neurotransmitters (the chemical signalling molecules in the brain) and have a specialised role to bind neurotransmitters like GABA and glutamate that are released at synapses.A key goal of this proposal is to investigate how the regulation of the delivery of cargo between different organelles is performed, characterising the molecular properties of the protein AP4 which we think is crucial for regulating the homeostasis of organelle networks and for the regulation of receptor signalling. When the AP4 complex goes wrong in humans this leads to a devastiating neurological disorder, causing intellectual disability, brain structural alterations, epilepsy, in addition to spastic paraplegia and gait problems. However we still don't know how AP4 complex dysfunction leads to this devastating disease. In particular we want to know how AP4 complexes help brain cells to regulate membrane delivery and the number, activity and location of the key membrane proteins (such as neurotransmitter receptors) in the plasma membrane of brain cells to control neuronal signalling. Studying the molecular mechanisms that underlie these regulatory processes will allow us to better understand how the brain works under healthy conditions. In addition because disrupted cargo delivery is implicated in many neurodegenerative and neuropsychiatric diseases, our proposed work may also lead to an improved understanding of diseases where membrane trafficking and synaptic function are altered such as in epilepsy, stroke, Alzheimer's disease, motor neuron disease, Huntington's disease, schizophrenia and autism.