- Title
- The role of early versus late gestational maternal immune activation in the aetiology of schizophrenia: establishing a rat model with a focus on cognitive symptomology and neuroinflammation
- Creator
- Meehan, Crystal Lea
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2018
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Schizophrenia is a debilitating disorder of neurodevelopmental origins that likely stems from the cumulative action of a range of genetic and environmental factors. Epidemiological evidence has identified maternal infection during gestation as one significant environmental risk factor for the development of the disorder. Evidence from animal models has further validated the link between maternal immune activation (MIA) in the absence of an active infection and the later life development of schizophrenia-like pathology in the offspring. In particular, work in mouse models has suggested that the gestational time at which MIA occurs can alter the behavioural and neurobiological phenotype displayed. Specifically, that MIA in late gestation is involved in schizophrenia-relevant cognitive dysfunction and altered NMDA receptor expression, whereas MIA in early gestation is more closely associated with behavioural deficits reminiscent of positive symptomology and dopaminergic neurotransmission. The aim of the current thesis was to extend the mouse findings to another species, the rat, and further explore the effects of MIA. In addition to producing a reliable rat model of schizophrenia where distinct behavioural and neurological phenotypes associated with schizophrenia are produced following MIA at either early or late gestational time-points (gestational day 10 or 19, respectively), the current thesis extends on previous work by examining the schizophrenia biomarker of mismatch negativity and assessing the neuroinflammatory state of offspring. Behavioural assessments revealed that MIA in either early or late gestation produced transient impairments in working memory and reductions in PPI. In these behavioural studies, there was no clear distinction between a dopamine and glutamate-related behavioural phenotype based on the gestational timing of exposure. However, early but not late gestation MIA did produce alterations in the dopaminergic system of males, as indicated by increased dopamine 1 receptor mRNA in the nucleus accumbens. EEG experiments demonstrated that although the male rat brain is able to generate human-like (adaptation-independent) mismatch responses (MMRs), and although MIA (regardless of gestational timing) does alter MMRs, it does not do so in a manner comparable with schizophrenia. Immunohistochemical techniques revealed that MIA does result in subtle neuro-immune changes in adult offspring, with an increase in microglial immunoreactivity identified in the frontal white matter of late, but not early, gestation MIA animals. Furthermore, a strong trend towards increased astrocyte immunoreactivity that approached significance was identified in the prefrontal cortex of late, but not early MIA offspring. The combined results have demonstrated that MIA during the chosen gestational time-points are sufficient to disrupt neurodevelopmental processes producing long-term alterations in behavioural and neuropathological measures relevant to schizophrenia. However, the phenotype characterised here deviates slightly from previous findings from mouse models indicating potential differences in the critical periods of neurodevelopmental susceptibility to MIA exposure between the rat and mouse. Importantly this research has provided insights into the underlying neuro-immune changes which may contribute to the behavioural abnormalities seen in adult MIA offspring and has provided evidence that MIA in rats can alter the prominent schizophrenia relevant electrophysiological biomarker of adaptation-independent MMRs, providing a basis to further investigate these measures and their underlying mechanisms.
- Subject
- schizophrenia; microglia; sensorimotor gating; neurodevelopment; mismatch negativity (MMN); auditory event-related potentials; deviance detection; adaptation; animal model; wistar rat; electroencephalography; telemetry; astrocyte; glutamate; GFAP; IBA1; IL-6; infection; thesis by publication; cytokine; neuroinflammation; maternal immune activation (MIA); poly (I:C); gestational timing; working memory; dopamine
- Identifier
- http://hdl.handle.net/1959.13/1385728
- Identifier
- uon:32284
- Rights
- Copyright 2018 Crystal Lea Meehan
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 5 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 154 KB | Adobe Acrobat PDF | View Details Download |