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The autism and schizophrenia associated genes CYFIP1 and Ahi1 in synaptic signalling and neuronal development

Davenport, EC; (2016) The autism and schizophrenia associated genes CYFIP1 and Ahi1 in synaptic signalling and neuronal development. Doctoral thesis , UCL (University College London).

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Abstract

Correct regulation of synaptic function is essential for normal brain activity. Disrupted synaptic signalling can result in a loss of neuronal contacts and altered morphology, leading to deficits in network activity and transmission; features of neuropsychiatric disorders. Indeed, defects in neuronal and synapse morphology are detected in autism and schizophrenia and thought to contribute to the characteristic behavioural abnormalities observed in these conditions. In this thesis the role of two neuropsychiatric disease associated proteins, CYFIP1 and Ahi1, in the regulation of synaptic function and neuronal morphology were investigated. First, this study revealed that CYFIP1 and CYFIP2 were enriched at excitatory synapses. Altering CYFIP1 gene dosage to model disease states showed that CYFIP1 affected dendritic complexity, spine morphology and spine actin dynamics. Inhibitory synapse integrity was also disrupted with increased CYFIP1 or CYFIP2 dosage. Secondly, genetic studies revealed a significant association of CYFIP1 with schizophrenia, contributing to the evidence that CYFIP1 is a risk locus for this condition. However, CYFIP1 schizophrenia-associated mutations identified here did not interfere with CYFIP1 localisation or protein interactions. Novel CYFIP1 knockout (KO) systems were characterised to further understand CYFIP1 function. Initial observations revealed CYFIP1 KO reduced viability and impaired F-actin levels in fast dividing cells while conditional KO of CYFIP1 in adult CA1 neurons disrupted dendritic complexity. Lastly, a novel Ahi1/HAP1/KIF5 trafficking complex was identified in brain. However, the trafficking of GABAARs, known HAP1/KIF5 cargo, was unaffected by altered Ahi1 expression. Nevertheless, Ahi1 was localised to synapses and Ahi1 knockdown enhanced dendritic complexity. In summary, this thesis provides evidence that altered expression or disease associated mutations in CYFIP1 and Ahi1 led to changes in synapse integrity and dendritic complexity, both of which may contribute to the development of the neurological symptoms observed in autism and schizophrenia.

Type: Thesis (Doctoral)
Title: The autism and schizophrenia associated genes CYFIP1 and Ahi1 in synaptic signalling and neuronal development
Event: University College London (UCL)
Language: English
Keywords: CYFIP1, Ahi1, autism, neuropsychiatric disorders, copy number variation, synapse stability, dendritic spines, dendritic morphology, actin
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/1475890
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