Epidemiological studies indicate that maternal vitamin D deficiency may be a candidate developmental risk factor for schizophrenia. For example, people born in winter/spring, urban environments and dark-skinned individuals whose parents migrated to cooler climates are all at increased risk of developing schizophrenia later in life. The biological plausibility that a low prenatal level of vitamin D has an adverse impact on the developing brain has been studied using a developmental vitamin D (DVD) deficient rat model. These animals display molecular and anatomical abnormalities in brain development and alterations in behaviour as adults. Compared with control rats, neonatal DVD-deficient rat brains are different in shape; displaying a thinner cortex and larger lateral ventricles. Moreover, the brains appear to be less differentiated. At adulthood, DVD-deficient rats show an enhanced sensitivity to novelty-, antipsychotic- and psychomimetic- induced locomotion. These observations have lead to the hypothesis that dopamine and/or glutamate neurotransmission may be altered in DVD-deficient rats. Thus, the main aim of this thesis was to further characterise the dopamine and glutamate neurotransmitter systems in DVD-deficient rats. DVD-deficiency resulted in sex and age specific changes in dopamine signalling. At birth, DVD-deficient rats showed altered dopamine metabolism in the forebrain providing the first report of altered dopamine function after DVD-deficiency. Female DVD-deficient rats displayed a post-adolescent (at 3 months of age) enhanced response to amphetamine-induced locomotion. Accompanying this behavioural sensitivity were decreased levels of dopamine 1 and 2 receptor density in the nucleus accumbens. The altered behaviour in female DVD-deficient rats was not associated with increased dopamine release in the prefrontal cortex, caudate putamen or nucleus accumbens. Although a similar increase in the behavioural sensitivity to amphetamine was not observed in male DVD-deficient adult rats, increases in the density of the dopamine transporter were observed in the caudate putamen and nucleus accumbens. However, when examined at a mature adult age (6 months) neither the enhanced response to amphetamine, receptor or transporter changes persisted. These results suggest that after puberty a transient change in dopamine receptor signalling manifests as an altered response to amphetamine under certain environmental and experimental conditions. Glutamate signalling was probed with the N-methyl-D-aspartate receptor antagonist MK-801. Adult male DVD-deficient rats showed an enhanced locomotor response to MK-801 and this persisted when examined at a mature adult age. Female DVD-deficient rats showed an enhanced response but this was only observed at the mature adult age examined. No behavioral differences were observed prior to adolescence. This behavioural sensitivity did not appear to be due to altered dopamine release after MK-801 in the prefrontal cortex and caudate putamen. Taken together, male DVD-deficient rats develop a locomotor sensitivity to MK-801 at an earlier age than DVD-deficient females. This behavioural alteration is not associated with altered dopamine function. The combined results from the studies in this thesis present a complex phenotype that suggests altered dopamine and glutamate interactions in DVD-deficient rats that are dynamic; demonstrating both age and sex specific traits. I speculate that the development of these behavioural and neurochemical alterations in DVD-deficient rats follows a similar temporal profile to the symptomology observed in schizophrenia patients. Both behavioural sensitivities to amphetamine and MK-801 are observed in schizophrenia in addition to a delayed onset of symptoms in females. This provides further support for a role of vitamin D in the developing brain and suggests that a transient deficiency can result in long-term behavioural and neurochemical alterations. Together this suggests that the DVD-deficient rat model may be an informative model for exploring the developmental vitamin D deficiency hypothesis of schizophrenia.
| Identifer | oai:union.ndltd.org:ADTP/285421 |
| Creators | James Kesby |
| Source Sets | Australiasian Digital Theses Program |
| Detected Language | English |
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