| Summary: | A critical open question in neuroscience is how neurons distinguish one another and form precise synaptic connections with their appropriate partners. Synaptic cell-adhesion molecules have been postulated to contribute to the establishment, assembly and maintenance of synapses. One family of cell-adhesion molecules, the Teneurins, are highly conserved and expressed in interconnected regions of the brain during development. Teneurins have been shown to regulate appropriate synaptic partner matching and synaptic assembly in Drosophila. In vertebrates, which have four Teneurin paralogues (Tenm1-4), Teneurins have been shown to play important roles in the establishment of functional visual circuits. However, their exact role in the initial establishment and maintenance of synapses in vertebrates is not yet known. In this thesis I explored the role of Teneurins, in particular of Tenm3, in vertebrate synapse formation. I found that all four members of the Teneurin family are partially localised at synapses of hippocampal neurons. Tenm3, which is selectively expressed in CA1 in the hippocampus, was found to be enriched in dendritic spines and in the dendritic shaft directly below the spine neck in CA1 pyramidal neurons. To examine the role of Tenm3 in synapse formation in vivo, a Tenm3 gene trap mutant was crossed to a Thy1-GFP reporter line, which expresses green fluorescence protein (GFP) in sparse CA1 neurons in the hippocampus. Unexpectedly, I found that Tenm3 mutant mice had significantly increased dendritic spine densities compared to wild type litter mates. This effect was the result of a general increase in spine density across all spine categories, however the largest relative increase was observed for mushroom spines, which are considered the most mature spine type. The results suggest that Tenm3 acts as a negative regulator of spine development and maturation and define this protein as an important mediator of appropriate synaptic connectivity.
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