Nerve cells in the brain rely on chemical signals called Wnts to keep their connections—synapses—from falling apart, and blocking those signals causes synapses to disappear. Synapses are the junctions where neurons communicate, and they constantly remodel throughout life to support learning and memory. But scientists know very little about what keeps mature synapses stable. This gap matters because in neurodegenerative diseases such as Alzheimer’s, synaptic loss occurs well before neurons die. Understanding how synapses are maintained could reveal why they fail in disease. This project will dissect the molecular chain of events through which Wnts protect synapses, and test how disrupting that process alters neural circuits and behaviour in animals. The work is fundamental science—it will not produce a therapy tomorrow. But if it reveals the specific proteins and signals that hold synapses together, it could eventually point to drug targets for conditions where synapses are fragile or degenerating. Similar fundamental discoveries about synaptic signalling have already shaped treatments for depression and epilepsy.
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The formation of functional synapses, points of contact between two nerve cells (neurons) is crucial for proper brain function. Synapses are very dynamic structures that grow, shrink and change shape through the entire life of the organism. A dialogue between the pre-synaptic neuron (neurotransmitter releasing cell) and its postsynaptic target (a neurotransmitter responding cell) is essential for the formation, growth and maintenance of synapses. Importantly, the formation of new synapses and the remodelling of old ones underlay important functions such as learning and memory. Moreover, recent studies suggest that synaptic loss precedes the death of neurons observed in several neurodegenerative diseases. However, little is known about how synapses are maintained or protected against injury. Our laboratory has been studying the function of secreted factors, called Wnts, in the maintenance of synapses. We found that Wnt blockade induces the loss of mature synapses indicating that Wnts are critical for their maintenance. In this grant proposal, we will examine the molecular mechanism by which Wnts regulate synaptic maintenance and how this process influences neuronal connectivity and animal behaviour. Our results could contribute to the development of therapeutic strategies for the treatment of diseases in which synapses are compromised.
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