Date of Award

2014

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Professor John L. Waddington

Second Supervisor

Dr Brian P. Kirby

Keywords

Schizophrenia -- genetics

Abstract

DTNBPl (dystrobrevin-binding protein-1) has been strongly identified as a susceptibility gene for schizophrenia and implicated in cognitive function. Downregulation of DTNBPl expression in dorsolateral prefrontal cortex (DLPFC) and hippocampal formation (HF) of patients with schizophrenia may represent a primary pathophysiological mechanism. Described as a 'hub', dysbindin associates into multiple complexes in the brain and exerts a wide variety o f functions implicated in early brain development and neuroplasticity. The expression pattern o f the different dysbindin isoforms varies with brain development, tissue areas and subcellular localisations, and may interact with different partners. Variations in DTNBPl more specifically associated with dysbindin-1A may contribute to early-onset and cognitive deficits. Dysbindin-fA, the full-length isoform, is primarily expressed during embryonic and early postnatal development in postsynaptic areas. Comparatively to sandy mutant mouse models, expressing no dysbindin proteins, phenotypic characterisation of dysbindin-1A knockout (KO) mice, on a C57BL/6J background, will help to clarify the function o f DTNBPl in schizophrenia. As constructed by GlaxoSmithKline (GSK), this mutant line shows sex-specific deficits, with female KO being more reactive to stressful situations and male KO showing hyperactivity on initial exposures to a novel environment that maybe related to some disruption to habituation and dysregulation o f DG-dependent working memory function (pattern separation). For both sexes these phenotypes occur concurrently with normal general physiological indices, sensori-motor gating, social behaviours, delay-independent working memory and attention, long-term memory and delaydependent working memory. Further investigations in the conditional floxed mutant, also constructed by GSK, may help to clarify the neural mechanisms underlying these features that implicate dysbindin-lA in schizophrenia-re la ted cognitive processes and stress reactivity.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

11.5 MB

Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2014.

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