- Title
- The combined impact of two developmental risk factors for schizophrenia on inhibitory and excitatory systems in a rat model
- Creator
- Leong, Angeline Jia Wen
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2022
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Individuals with schizophrenia have impairments in cognitive domains such as working memory. These are found in association with reduced gamma power in electroencephalogram (EEG) studies when patients perform a working memory task. Various studies have demonstrated that maternal immune activation (MIA) and adolescent cannabinoid exposure (ACE) are major risk factors for schizophrenia. The aim of the current thesis was to characterise how inhibitory interneuron function, gamma oscillations and cognitive performance are affected in a combined developmental risk factor (i.e. MIA + ACE) ‘two-hit’ rat model for schizophrenia. In this two-hit animal model, pregnant Wistar rats were given poly(I:C) intravenously at gestational day 19 to induce MIA. Half of the offspring were then subsequently injected with synthetic cannabinoid HU210 in early adolescent (at P35 onwards) to induce ACE, whilst the second half received vehicle treatment. This model allowed us to comprehensively investigate underlying molecular and physiological mechanisms, and delineate the impact on cognitive function. It was hypothesised that combined MIA and ACE will induce a schizophrenia-like phenotype in rats which is preceded by disrupted parvalbumin (PV) interneuron function, altered gamma oscillations, and impaired cognitive performance. Gene expression was examined in the medial prefrontal cortex (mPFC) at P50 (late adolescent), P60 (young adult) and P90 (adult) using fluidigm qPCR. The study found that Gad1 mRNA, which encodes for GAD67, was only reduced at P50 in MIA- and ACE-alone rats, compared to the control group. Two-hit animals did not demonstrate a synergistic effect on Gad1. MIA-treated rats also had decreased Pv mRNA at P60, but not at P50 and P90, compared to controls. Interestingly, brain-derived neurotrophic factor (Bdnf) mRNAs were increased at P90 in two-hit animals, but not in MIA- and ACE-alone groups, compared to the control group. Surprisingly, immunoblot analyses did not find GABAergic interneuron markers altered in the mPFC at P90. Furthermore, the PV interneuron density in the mPFC sections was also not altered in MIA-treated animals. Additionally, short-term spatial memory and gamma power were assessed in the two-hit rat model. During adulthood, animals were subjected to a T-maze task, a spontaneous alternation paradigm based on the rat’s innate preference to explore a novel arm of the maze. MIA-only treated rats did not show preference for a novel arm in the test phase, unlike the control rats, thus implicating impaired spatial working memory. EEG was recorded to assess the gamma oscillations in these rats. Poly(I:C)-treated rats had reduced low gamma power (30- 80 Hz) whilst HU210-treated male rats had increased high gamma power (80 – 200Hz), upon re-entering. Two-hit rats did not exhibit synergistically altered gamma power during the test phase. In conclusion, these results highlight the distinct effects of MIA and ACE on GABAergic interneuron markers, working memory performance, and gamma oscillations in a two-hit rat model for schizophrenia. This study has provided further evidence to support MIA and ACE as critical factors in the development of schizophrenia-like behaviours and brain changes. Importantly, this study also showed that these deleterious insults may have long-lasting impacts on the GABAergic interneuron functions and potentially impair cognitive performance.
- Subject
- schizophrenia; maternal immune activation; adolescent cannabinoid exposure; GABAergic interneurons; gamma oscillations; working memory
- Identifier
- http://hdl.handle.net/1959.13/1508709
- Identifier
- uon:56148
- Rights
- Copyright 2022 Angeline Jia Wen Leong
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 6 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 512 KB | Adobe Acrobat PDF | View Details Download |