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Regulation of hippocampal synapse formation and specificity


Synapse formation is a complex process that requires coordination of multiple steps. The factors that control this process are only beginning to be understood. Several molecules have already been implicated, including cell adhesion molecules like cadherins, synCAM, and neuroligin and its binding partner [Beta]-neurexin as well as secreted factors like FGF22, thrombospondin, and Wnts. Wnts are an intriguing class of molecules that have been reported to be involved in everything from regulating cell fate in stem cells to cancer. However, Wnts have only recently been investigated in synapse formation. Studies exploring Wnts in synapse formation have yielded conflicting results and it is unclear whether this disagreement is a result of the variety of systems or the variety of Wnt proteins used in these studies. I show here that Wnts are expressed in all regions of the forebrain during the first two weeks of postnatal rodent development, a time at which synapses rapidly form. Using hippocampal cultures, I show that several Wnts expressed in the hippocampus can mediate various signaling pathways. We show that Wnts 3a, 7a, and 7b, which are able to upregulate [Beta}-catenin, have a positive effect on synapses, while Wnt5a, which is unable to stabilize [Beta} -catenin, has a negative effect on synapses. This bidirectional control of synapses is likely due to the differential effects of these Wnts on stabilization of [Beta}-catenin. In addition to the coordinated assembly of synapses, it is also important for these synapses to be targeted to the correct postsynaptic cell. This directed synapse formation creates functional circuits of the brain. In collaboration with Megan Williams, we explore the specificity of the DG synapse in vitro using a combined functional and anatomical approach. We find that DG neurons in the absence of axon guidance cues make more synapses and evoke larger postsynaptic currents in their correct postsynaptic targets, CA3 neurons, than in any other cell type. These results lay the groundwork in which to explore potential mediators of synaptic specificity, including Wnts

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