Using Drosophila to model schizophrenia symptoms

Abstract

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.

Date of Award	12 May 2020
Original language	English
Awarding Institution	The University of Bristol
Supervisor	James J L Hodge (Supervisor) & Ingeborg Hers (Supervisor)