De Medeiros Lopes, D; (2015) The role of Wnt signalling in synapse maintenance in the hippocampus. Doctoral thesis , UCL (University College London).

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Abstract

Wnt signalling is well known for its role during development and formation of central synapses. Interestingly, many studies have demonstrated that Wnts and their receptors are continuously expressed after development in the adult brain, suggesting that Wnt signalling might play a role in synaptic maintenance during adulthood. Our lab has demonstrated that Dickkopf-1 (Dkk1), an endogenous Wnt antagonist, can rapidly induce the disassembly of synapses in hippocampal cultures (Purro et al., 2012). In addition, recent studies demonstrated that Dkk1 expression is increased in the brain of Alzheimer’s disease (AD) patients, as well as in some transgenic mouse models of AD, which coincides with synaptic loss and impaired memory. These results suggest that Wnt signalling may be involved in the maintenance of synapses in the adult brain. To investigate the role of Wnt signalling in the adult central nervous system, I used an inducible transgenic mouse line that expresses Dkk1 in the hippocampus under the control of tetracycline. I found that induction of Dkk1 expression in the hippocampus of adult mice leads to profound synaptic changes. Dkk1 expression induces the disassembly of excitatory synapses in the hippocampus, without affecting inhibitory synapses or compromising cell viability. Morphological analyses of dendritic spines showed a decrease in number and size of spines in the hippocampus CA1 area. Supplementing these findings, behavioural analysis showed that adult Dkk1 transgenic mice exhibit impaired spatial and long term memory. Furthermore, in this study I also give insight to the mechanism of action of Dkk1, demonstrating that Dkk1-mediated synaptic disassembly is dependent on protein degradation. In summary, my studies demonstrate that Wnt signalling is crucial for synaptic maintenance in the adult hippocampus and for normal hippocampal-dependent memory.

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