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Title: Cell type-specific functions of neuropsychiatric disease-associated gene CYFIP1 in the brain
Author: Drew, James
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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The shape and connectivity of neurons underlies all higher brain functions and abnormalities in these features are a hallmark of many neuropsychiatric disorders. In the brain, functional neural networks arise through an interplay between intrinsic intracellular processes and interactions between neurons and other cell types, including glia. CYFIP1 is a neuropsychiatric disease-associated gene with established roles in actin remodeling and local protein translation. Previous studies have shown that altered expression of CYFIP1 regulates neuronal morphology, connectivity and synaptic plasticity, although it is currently unclear to what extent these represent cell-autonomous effects. Additionally, the embryonic lethality of CYFIP1 has precluded the study of complete CYFIP1 loss in vivo. This thesis aims to address some of these questions using transgenic mice harboring cell type-specific deletions of CYFIP1. Firstly, an excitatory neuron-specific CYFIP1 knockout was generated. Loss of neuronal CYFIP1 led to stunted dendrite growth in vitro and in vivo and to differential effects on axon growth. Migration of neuronal progenitor cells during embryogenesis was unaffected in this model. Investigation revealed normal synapse formation in cultured neurons lacking CYFIP1. However, several developmentally-dependent changes were observed in vivo, including immature spine morphology and an increase in post-synaptic inhibition in young adult mice. Lastly, a novel role for CYFIP1 in microglia was investigated. Using a live-imaging assay of acute slices, a role for CYFIP1-associated actin remodeling complexes in microglial motility was established. A microglia-specific CYFIP1 knockout mouse showed changes in microglial morphology and a specific defect in surveillance motility. These results provide evidence for novel functions of CYFIP1 in neurons and microglia that will inform our understanding of the cellular interactions underlying disorders such as autism and schizophrenia.
Supervisor: Kittler, J. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available