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

Lead Research Organisation: University College London
Department Name: Cell and Developmental Biology

Abstract

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.

Technical Summary

The structural and functional plasticity of synapses underlies fundamental brain functions including learning and memory. Defects in synaptic plasticity are correlated with cognitive decline in neurodegenerative conditions such as Alzheimer's disease (AD). Great progress has been made in unravelling the mechanisms controlling synaptic plasticity at central synapses. However, our understanding of how synapses are modulated in the healthy and diseased brain remains limited.

Wnt secreted proteins are emerging as key modulators of synaptic connectivity. Our lab has made significant contributions to this field. Our latest studies revealed a crucial role for Wnt signalling in synaptic plasticity, as inhibition of endogenous Wnts blocks long-term potentiation in the hippocampus. We also showed that Wnt7a signals through the Frizzled-7 receptor to promote synaptic plasticity. Wnt-Fz7 signalling triggers similar pathways as NMDAR activation. Based on extensive pilot data, we propose that Wnt signalling together with activation of NMDARs regulates synaptic potentiation. We also found that Fz7 is affected in AD mouse models when synaptic deficits begin to emerge. These results suggest that deficiency in the levels of Fz7 receptor may contribute to synaptic plasticity defects in AD.

The central aim of this proposal is to unravel the function of Fz7 in synaptic plasticity in the hippocampus, and to examine how deficiency in Fz7 affects synapses in AD models. We will address three main objectives: 1) To determine the molecular mechanisms by which Fz7 regulates NMDAR-mediated synaptic plasticity; 2) To examine the impact of Amyloid-Beta on Fz7 and associated proteins during synapse degeneration; 3) To investigate whether enhanced Fz7 signalling protects synaptic plasticity and memory in AD models.

Our studies will provide new mechanistic insights into how synaptic modulators regulate synaptic plasticity and whether they protect synapses in AD models.

Planned Impact

Our studies will inform us how receptors for synaptic modulators regulate synaptic plasticity and memory. Proteins identified in our studies including analyses of the synapse proteome will inform scientists on new potential mechanisms controlling synapse biology and cell signalling. This research will benefit scientists studying the molecular mechanisms controlling synaptic plasticity and synaptic dysfunction in neurodegenerative conditions such as Alzheimer's disease. In addition, our studies will also benefit researchers working on the role of signalling molecules in diverse cellular processes.

The immediate beneficiaries of this research are the scientists working in the project, as they will receive training in a wide range of state-of-the-art research approaches, which will significantly improve their career prospects and enable them to apply for independent fellowships and faculty positions.

Our studies could also benefit the pharmaceutical industry for the design and testing of drugs that could protect synapses in synaptopathies and neurodegeneration. Ultimately our research program will benefit people suffering from neurodegenerative diseases as our studies could lead to a better understanding of how to restore or ameliorate synaptic plasticity defects.

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