Boyle, K.A.; (2010) The role of Wnt signalling in hippocampal synapse formation and function. Doctoral thesis , UCL (University College London).

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Abstract

Wnt proteins are a large and diverse family of secreted signalling factors that play key roles in the development of the nervous system, including control of neuronal proliferation and differentiation, axon guidance, dendritogenesis and synaptogenesis. Despite recent advances in our understanding of Wnt function at synapses, key questions remain unanswered. For example the role of Wnt signalling in central postsynaptic development remains unclear, as does the specificity of Wnts for regulating different sub-types of synapse. The aim of this thesis was to investigate the role of Wnts in regulating the formation and function of central glutamatergic and GABAergic synapses in the rodent hippocampus, using complementary cell biological and electrophysiological approaches. I find that Wnt7a specifically promotes the formation of excitatory glutamatergic synapses in cultured hippocampal neurons, with no effect on inhibitory GABAergic synapses. Furthermore, specific postsynaptic activation of Wnt signalling results in increased dendritic spine size, increased clustering of the postsynaptic protein PSD-95 and increased presynaptic innervation of dendritic spines. In contrast, GABAergic synapses are unaffected by Dishevelled-1 expression. I also find that endogenous Wnt signalling regulates excitatory synaptic function. Acute blockade of endogenous Wnt signalling using the Wnt antagonists sFRP1, 2 and 3 results in a decrease in mEPSC frequency and evoked release probability at glutamatergic synapses, with no effect on GABAergic synapses. A similar decrease in evoked release probability is observed at glutamatergic Schaffer collateral-CA1 synapses in hippocampal slices from Wnt7a-/-; Dvl1-/- double knockout mice. Finally, I demonstrate that a prolonged reduction in glutamatergic release probability caused by chronic Wnt signalling blockade elicits a homeostatic increase in glutamatergic synapse number that acts to maintain normal levels of excitatory signalling. In conclusion, the work presented in this thesis significantly advances our understanding of the role of Wnts at central synapses. Wnt signalling regulates multiple processes throughout the lifetime of an excitatory glutamatergic synapse. Wnt7a promotes the formation of excitatory synapses through the co-ordinated clustering of pre- and postsynaptic proteins. Postsynaptic Wnt signalling can directly regulate excitatory postsynaptic formation at central synapses, and can also signal back to the presynaptic side. Endogenous Wnt signalling plays a role in maintaining normal levels of glutamate release, and chronic perturbation of this signalling results in compensatory changes in synapse density.

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