Phenotypic characterisation of a novel mutant mouse with target deletion of dysbindin-1A in relation to the schizophrenia risk gent DTNBP1.
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.
First SupervisorProfessor John L. Waddington
Second SupervisorDr Brian P. Kirby
CommentsA thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2014.
Published CitationPetit E. Phentoypic characterisation of a novel mutant mouse with target deletion of dysbindin-1A in relation to the schizophrenia risk gent DTNBP1 [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2014.
- Doctor of Philosophy (PhD)