Date of Award

2014

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Pofessor David R. Cotter

Second Supervisor

Dr Melanie Föcking

Third Supervisor

Dr Gerard Cagney

Funder/Sponsor

Science Foundation Ireland and Stanley Medical Research Institute

Keywords

Schizophrenia -- etiology, Myelin Proteins

Abstract

Accumulating evidence from epidemiologic and clinical findings report that both exposure to prenatal inflammation and prenatal iron deficiency significantly increase the risk of developing Schizophrenia in the offspring. Abnormalities in myelin are the most robust neuropathological findings in post-mortem human Schizophrenia, however the exact mechanisms at the protein and pathway levels owing to the myelin deficits are largely unknown.

Animal models offer a fruitful approach to study the neurobiological basis of brain disturbances relevant to Schizophrenia. Furthermore, they are vital tools for testing hypotheses which cannot be directly assessed in human subjects for ethical and technical reasons. The advantage of animal models universally lies in the fact that they present a more accessible form o f a complex human phenomenon. Animal models of prenatal inflammation and prenatal iron deficiency converge on the evidence for abnormal myelin in Schizophrenia. Therefore, they represent advantageous avenues for myelin research, the discovery of novel myelin related mechanisms and putative drug targets.

We hypothesised that myelin dysregulation would be present in post-mortem human Schizophrenia and in preclinical animal models of prenatal inflammation and prenatal iron deficiency. Using predominantly discovery-based proteomics, we aimed to reveal signalling pathways to explain the myelin deficits and provide more insight into the observed myelin pathology in Schizophrenia.

Our data suggests a decrease in myelin specific, and myelin related proteins in the prefrontal cortex of adult rodent offspring prenatally exposed to inflammation or iron deficiency which could relate to the myelin abnormalities present in post-mortem human Schizophrenia. A collective dysregulation was also observed in core metabolic and mitochondrial signalling, aspects of the mitogen activated protein kinase pathway, and evidence for oxidative stress. In the white matter of the dorsolateral prefrontal cortex of post-mortem human Schizophrenia we reported pathways affected by differential protein expression to include transport, signal transduction, energy pathways relating to sugar, lipid and carbohydrate metabolism, cell growth and maintenance. Additionally, upon enriching for the myelin proteome in the dorsolateral prefrontal cortex white matter we found significant changes in core myelin specific proteins accompanied by changes in protein signalling and protein trafficking pathways.

Considering Schizophrenia unfolds during the late period of brain maturation while myelination is still continuing, such as adolescence, we also determined protein expression in the prefrontal cortex of adult rodents following exposure to adolescent Risperidone to shed light on biological mechanisms pertaining to antipsychotic treatment which may also lie at the heart of Schizophrenia myelin neuropathology. Our data suggest that Risperidone treatment in adolescence following exposure to prenatal inflammation or prenatal iron deficiency could prevent myelin and metabolic/mitochondrial related protein changes implicating a positive role of early intervention treatment to prevent these changes.

The presented data contribute to the composition of a scenario that may lead to a better understanding of Schizophrenia pathogenesis. The collection of protein alterations identified here reinforces the importance of myelin in Schizophrenia, and reveals a number of new potential markers that may contribute to the understanding of the pathogenesis of this complex disease.

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

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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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