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Title: Using Drosophila to model schizophrenia symptoms
Author: Hidalgo Sotelo, Sergio I.
ISNI:       0000 0004 9347 1636
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2020
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Schizophrenia is characterized by the presence of several symptoms including social withdrawal, cognitive impairments and psychosis. Additionally, other less known traits are observed such as olfactory deficiencies, locomotor dysfunction and circadian and sleep disruption. It is unclear what are the factors involved in the progression and onset of these symptoms. Schizophrenia shows high heritability and several genes, among those that have been associated with this disorder, are related to calcium (Ca²⁺) signalling pathways. Genetically modified animal models of schizophrenia have started to be used to uncover the molecular and physiological mechanisms underlying the disease. However much remains to be elucidated. In this thesis the fruit fly, Drosophila was used to model some aspects of the classical and non-classical symptoms of schizophrenia, including olfaction, social interactions, locomotion, sleep and circadian locomotor rhythms. Characterisation of the previously proposed Drosophila schizophrenia model based on the Dystrobrevin binding protein-1 (DTNBP1), Dysbindin (Dysb) mutant, was used as a proof of principle. The results were compared to characterisation of two new genes associated with schizophrenia: the Rab-3 interacting molecule-1 (RIMS1) and the calcium channel subunit α1B (CACNA1B) called Rim and cacophony (cac) respectively in flies. Manipulating the expression of these genes had different contributions to behaviours that were reminiscent of some schizophrenia behavioural symptoms. Olfactory performance was assessed using single-fly video tracking exposed to an aversive odorant and social interactions were assessed by using a social space paradigm to measure the clustering of the flies. Both, olfaction and social behaviours were reduced in the Dysb and Rim mutants. Moreover, the effect of Rim on social behaviour was explained by a dysfunction in the olfactory system, accompanied by reduced terminal area and impaired Ca²⁺ handling of the projections sent by the antennal lobe projection neurons (AL PNs) reaching the lateral horn (LH). Rim and cac manipulations differentially contributed to learning and memory which was assessed by an aversive olfactory conditioning assay. Rim knock-down in the mushroom body spared memory, while cac knock-down impaired short- and intermediate-time memory. The memory defect of cac mutants was explained by impaired Ca²⁺ handling namely reduced Ca²⁺ influx upon a depolarizing stimulus. Using the Drosophila Activity Monitoring (DAM) Rim and cac mutants were shown to display circadian rhythm and sleep deficits. The changes observed in the Rim mutant were accompanied by impaired day/night remodelling of the small-LNvs (s-LNvs) dorsal terminals and impaired day/night PDF neuropeptide release. The results of this thesis add more information to the role of synaptic proteins related to Ca²⁺ signalling in schizophrenia-like pathology. Moreover, this work demonstrates the suitability of Drosophila genetic models to help understand the molecular and physiological basis of schizophrenia.
Supervisor: Hodge, James ; Hers, Ingeborg Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available