Year

2015

Degree Name

Doctor of Philosophy

Department

School of Medicine

Abstract

The development of schizophrenia is thought to involve an interaction of genetic susceptibility and environmental factors. In particular, immune insults have been suggested as relevant environmental impacts, with evidence of cytokine alterations in schizophrenia patients and an emerging role for cytokines in the brain. Neuregulin 1 (Nrg1) represents one potential candidate vulnerability gene and although murine and human studies indicate the potential for a Nrg1 mutation to influence immune function, the response to a direct immune stimulus has not been studied. The aim of the present study was to determine if a mutation in the Nrg1 gene altered sensitivity to an immune challenge by changing the peripheral cytokine response and corresponding cytokine levels in the brain.

Together these data demonstrate strong cross talk between the immune system and the brain. The elevated IL-6 plasma level found in the Nrg1 Het mice was consistent with increased levels of IL-6 found in several studies on schizophrenia patients, as well as in humans carrying a Nrg1 mutation. While G-CSF has not been directly studied, a peripheral role is implicated in schizophrenia in relation to side effects caused by antipsychotic medications. The implications of reduced IL-6 and GCSF as found in the brain are yet to be understood, however these results confirm a dysfunction of cytokines in the brain of Nrg1 Het mice. Although the detected alterations in the studied signalling pathways should be considered carefully due to study limitations; a potential dysregulation of the PI3K/Akt pathway is indicated. It remains to be determined whether these changes have neuromodulatory functions and can influence schizophrenia-relevant neurotransmission and behaviour. This study demonstrated, however, that peripheral cytokines and brain cytokines are perturbed when a Nrg1 mutation is combined with a direct peripheral immune stimulus, similar to previous reports in humans, in a plausibly schizophrenia-relevant manner.

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