Anane, D.; (2012) The role of Wnt signalling in excitatory hippocampal synapse formation and function. Doctoral thesis , UCL (University College London).

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Abstract

The formation of a functional neural network is dependent on the correct assembly of cell-cell contacts. Apposition of pre and post synaptic terminals is a highly regulated process culminating in the formation of the functional junction points called synapses. Whilst much is understood of the processes involved in bringing axon and target together less is understood of the mechanisms controlling synapse assembly and maintenance. Wnts are highly glycosylated secretary proteins which have been demonstrated to be involved at several stages of the developing nervous system. Through a range of signalling pathways Wnts are able to produce cellular effects including embryonic patterning, fate and movement. Much recent research has been focused on the role of Wnts in synapse formation and function. In this thesis I present data from hippocampal cultures showing Wnt7a regulation of excitatory synapses. Exposure of developing hippocampal neurons to Wnt7a results in an increase in the density of surface GluA1, GluA2 and GluN1 puncta on dendritic spines. Wnt7a also regulates the co-localisation of postsynaptic glutamate receptor puncta with presynaptic sites labelled with vesicular glutamate transporter protein (vGlut). Interestingly the Wnt7a mediated increase in excitatory synapse formation is no longer present on neurons from mature cultures. At the main postsynaptic site of excitatory synaptic transmission I identified Wnt7a and Dvl mediated maturation of glutamatergic receptor localisation. Both exogenous Wnt7a and overexpression of Dvl in 14DIV hippocampal cultures caused an increase in the size and number of receptor puncta located on spines and the proportion of spines containing GluA1, GluA2 and GluN1 puncta. In my thesis I also present in vivo functional data, using animals null for both Wnt7a and Dvl expression. These animals demonstrate defects in evoked post synaptic currents and paired pulse ratio at the CA3-CA1 hippocampal synapse. In conclusion this report demonstrates the crucial role of Wnt7a – Dvl signalling in the regulation of excitatory synapse formation in the hippocampus. Furthermore amongst the myriad ways in which Wnt7a-Dvl signalling affects development of the CNS, Wnt7a acts directly at postsynaptic sites to increase synaptic strength.

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