Date of Award

2012

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Professor John L. Waddington

Second Supervisor

Colm O'Tuathaigh

Keywords

Schizophrenia, genetics

Abstract

Developmental models of schizophrenia propose that genes involved in neurodevelopment and/or environmental insults during early life result in brain dysmorphogenesis and subsequent pathophysiology, with gene (G) * environment (E) interactions proposed to mediate vulnerability to psychosis. The studies described in this thesis address: (i) G x E interactions between the schizophrenia risk gene NRG1 and specific, experimentally controlled environmental interventions; and (ii) putative pathophysiological mechanisms relating to dopaminergic function. Two paradigms were employed: (a) constitutive mutants with heterozygous deletion of NRG 1 to study interactions with prenatal immune challenge via administration of Poly I:C to pregnant dams with subsequent cross-fostering; and (b) conditional mutants with selective ablation of D1 dopamine receptors in forebrain vs. striatal vs. cortical brain areas to study the relative functional roles of these regions. In each case, behavioural phenotypes related to schizophrenia were studied, (a) NRG1 mutation interacted with maternal Poly I:C [G x Ej] in relation to open field behaviour, sociability and spontaneous alternation; NRG1 mutation interacted with cross-fostering [G x E2] in relation to social novelty preference and total entries in the Y-maze; maternal Poly I:C interacted with cross-fostering [E1 x E2] in relation to open field behaviour, sociability and PP1; NRG1 mutation interacted with Poly I:C and cross-fostering [G x E1 x E2] in relation to PPI. (b) Open field behaviour was associated primarily with D1 receptors in the striatum; social novelty preference was associated primarily with interplay between cortically-mediated social memory and striatally-mediated social anxiety; spontaneous alternation in the Y-maze was associated with D1 receptors in the hippocampus; total arm entries in the Y-maze was associated with D1 receptors in the striatum. Constitutive and conditional mutant mouse models are critical tools for the investigation of G x E interactions and putative pathophysiological processes in neuropsychiatrie disorders, as they enable the systematic examination of specific hypotheses within defined biological systems.

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Comments

Submitted for the Award of Doctor of Philosophy (PhD) to the Royal College of Surgeons, 2012.

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