Dickins, EM; (2012) Wnt Signalling in the Regulation of Synapse Formation and Maintenance. Doctoral thesis , UCL (University College London).

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Abstract

The formation of functional neural circuits depends upon a huge excess of synapses forming, many of which are subsequently eliminated in an activity-dependent manner. Critically, robust mechanisms must be in place to ensure selected synapses are maintained. The coordinated gain, loss and maintenance of synapses require a complex molecular dialogue between pre and postsynaptic neurons involving multiple signals. In addition to establishing functional neuronal circuits, normal brain function requires the correct balance of excitatory and inhibitory synapses. The distribution of excitatory and inhibitory inputs on a single neuron impacts significantly on its output, which in turn determines circuit formation and function. Whilst progress has been made in elucidating mechanisms that regulate synapse assembly, disassembly and maintenance, and the ratio between excitatory and inhibitory synapses, many aspects remain poorly understood. Wnt proteins are a diverse family of secreted glycoproteins known to stimulate synaptogenesis via Gsk3â. The aim of my thesis has been to further characterize the Wnt signaling pathway and determine whether Wnt7a is a pan-synaptogenic factor or if it preferentially stimulates the assembly of excitatory synapses. I have also explored a role for Wnt-mediated synaptic maintenance in mature synapses. My studies reveal that Wnt7a signals through a divergentcanonical Wnt pathway that is independent of transcription to specifically regulate presynaptic differentiation of excitatory synapses; inhibitory synapses are not affected. I also found that blockade of endogenous Wnt induces a rapid loss of synapses. Synapse disassembly was revealed by a coordinated loss of multiple pre- and postsynaptic proteins and neurotransmitter release sites. Ultrastructural analyses of remaining synapses revealed significant shrinkage of the active zone and postsynaptic density. To further explore synapse disassembly during Wnt-blockade, I imaged mature neurons expressing VAMP2-mRFP using time-lapse microscopy. Here I found that blockade of endogenous Wnt signaling rapidly induces disassembly of stable synaptic vesicle clusters. My results demonstrate that Wnt signaling plays two roles in hippocampal neurons. Firstly, Wnts promote the assembly of nascent excitatory synapses in young cultures. Secondly, Wnt signaling is required for synaptic maintenance in mature neurons. Synaptic maintenance is a novel role for Wnt signaling at synapses and this thesis work provides new insights into the mechanisms by which Wnt signaling modulates synapses in hippocampal neurons.

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