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

点击翻译按钮获取中文摘要

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.