Defining the role of Wnt-Fz7 signalling in long-term plasticity in health and disease

脑细胞或神经元之间的有效沟通是大脑功能所需的基本过程。这是通过称为突触的神经元之间的专门接触实现的。突触之间的交流水平根据神经元接收到的刺激而变化。这种突触通讯的调节被称为突触可塑性，这一过程是学习和记忆等关键功能的基础。突触可塑性的一种模式，被称为长期增强（LTP），增加了突触通信的强度。在这个过程中，一个关键分子是神经递质谷氨酸，它与受体结合，充当突触表面天线的分子，将信息传递到细胞内部。谷氨酸与位于突触上的特定受体（称为NMDA受体）的结合对神经元的连通性和突触增强具有深远的影响。这个过程涉及到基本的大脑功能，如学习和记忆。在阿尔茨海默病（AD）中，突触神经元之间的连通性在疾病的早期阶段受到严重影响。几项研究表明，突触的减弱会导致这些微小结构的丧失，从而导致患者的记忆障碍和执行基本任务的困难。尽管近年来在控制突触连接机制的科学研究方面取得了广泛的进展，但我们对健康大脑和AD等疾病中突触如何调节的理解仍然非常有限。我们的研究小组一直在研究一组叫做Wnts的蛋白质的功能。这些分子由细胞释放，促进神经元之间连接的形成。我们最近发现Wnt蛋白存在于突触中，并调节海马体突触的形成和大小，海马体是在学习和记忆中起核心作用的大脑区域。我们的最新工作也表明，wnt是突触可塑性的重要调节剂，依赖于NMDA受体。此外，我们的研究已经导致鉴定Wnt受体介导这种形式的突触可塑性。然而，wnt通过这些受体影响突触可塑性的确切分子机制尚不清楚。在当前的项目中，我们将解决这一核心问题，以推进这一领域的科学知识。我们最近的研究表明，在阿尔茨海默病小鼠模型的大脑突触中，wnt的受体减少了，这种模型已经被开发出来模拟疾病。这一发现与Wnt分子缺乏导致突触缺陷，从而导致AD患者记忆障碍的假设一致。在这个项目中，我们还将研究这种Wnt受体对AD小鼠模型突触缺陷的贡献，并测试这种受体的调节是否能恢复记忆。我们的研究可能对开发恢复阿尔茨海默病记忆的策略具有重要意义。

Efficient communication between brain cells or neurons is a fundamental process required for brain function. This is achieved through specialised contacts between neurons called synapses. The level of communication between synapses varies according to the stimuli received by the neuron. Modulation of this synaptic communication is called synaptic plasticity, a process that underlies crucial functions such as learning and memory. One mode of synaptic plasticity, called long-term potentiation (LTP), increases the strength of synaptic communication. A critical molecule in this process is the neurotransmitter glutamate which binds to receptors, molecules that act as surface antennas at synapses to convey information to the inside of the cell. Binding of glutamate to specific receptors located at the synapse, called NMDA receptors, has profound effects on the connectivity of neurons and on synaptic potentiation. This process is involved in fundamental brain functions such as learning and memory. In Alzheimer's disease (AD), the connectivity between neurons at synapses is profoundly affected in early stages of the disease. Several studies suggest that the weakening of synapses contributes to the loss of these tiny structures, resulting in memory impairment and difficulties in performing basic tasks in patients. Despite the extensive progress made in recent years in scientific research studying the mechanisms that control synaptic connectivity, our understanding of how synapses are modulated in the healthy brain and in conditions such as AD remains very limited. Our research group has been studying the function of a group of proteins called Wnts. These molecules are released by cells and promote the formation of connections between neurons. We recently found that Wnt proteins are present at the synapse and modulate the formation and size of synapses in the hippocampus, a brain area that plays a central role in learning and memory. Our latest work has also demonstrated that Wnts are important modulators of synaptic plasticity that depends on NMDA receptors. Furthermore, our studies have led to the identification of a Wnt receptor that mediates this form of synaptic plasticity. However, the precise molecular mechanisms by which Wnts influence synaptic plasticity through these receptors are not well understood. In the current project, we will address this central question to advance scientific knowledge in this area. Our recent studies demonstrate that the receptor for Wnts at the synapse is decreased in the brain of mouse models of AD, which have been developed to mimic the disease. This finding is in agreement with the hypothesis that deficiency in Wnt molecules contributes to synaptic defects, resulting in memory impairment in AD. In this project, we will also investigate the contribution of this Wnt receptor to synaptic defects in AD mouse models and to test whether modulation of this receptor restores memory. Our studies could have important implications for developing strategies to restore memory in Alzheimer's disease.