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Title: Disrupted-in-schizophrenia 1 (disc1) regulates development of the hypothalamus and its associated behaviours
Author: Sharples, Lucy
ISNI:       0000 0004 9356 4584
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2020
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Understanding how the genetic risk factor Disrupted-in-schizophrenia 1 contributes to neuropsychiatric disorders will help direct therapeutic efforts. Disc1 functions in neurogenesis and neuronal migration. Defects in early neurodevelopment are thought to be a contributing factor in neuropsychiatric disorders. Our group previously demonstrated that ENU-generated disc1Y472X/Y472X mutants have alterations in hypothalamic development from 2 days post fertilisation. Critically, behaviours relating to the hypothalamic-pituitary-interrenal (HPI) axis such as stress responses were also perturbed in larvae and adult. Here, we generated a novel disc1exon6/exon6 CRISPR knockout line with a frameshift mutation closer to the human translocation breakpoint. Following mutant validation, we characterised previously identified hypothalamic markers and found altered expression of retinal homeobox 3 and steroidogenic factor 1 (sf-1/ff1b). In addition, we identified increased expression of oxytocin in the developing hypothalamus. Behaviourally, a decrease in feeding and hunting behaviour was observed in both disc1Y472X/Y472X and CRISPR-generated disc1exon6/exon6mutant larvae. Sleep regulation was altered in disc1Y472X/Y472X only. Conversely, only disc1exon6/exon6mutants had maladaptive responses to acoustic and light stimuli as larvae, and to a novel environment as adults. These behaviours are associated with hypothalamic function and relevant to neuropsychiatric comorbidities such as eating disorders, insomnia, and anxiety. Using immunostaining for phosphorylated ERK as a measure of neuronal activity, we noted that loss of disc1 led to significant increases and decreases in neuronal activity in different neuronal populations in 7 dpf larvae. Regions of interest (ROIs) with increased activity included the forebrain and cerebellum, while ROIs with decreased activity included hypothalamic and connected regions. Finally, GSK-3ß inhibition during a critical time window normalised ff1b expression in disc1Y472X/Y472X mutant embryos, with later effects on neuronal activity and feeding behaviour at larval stages. This study demonstrates the validity of zebrafish in neuropsychiatric disease research and characterises novel neurodevelopmental and hypothalamus-associated behavioural functions of disc1.
Supervisor: Wood, Jonathan ; Roy, Sudipto Sponsor: A*STAR
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available