Epidemiological evidence from season of birth and migrant studies has led to the proposal that developmental vitamin D3 (DVD) deficiency may be a risk factor for schizophrenia. Concurrently, there has been recent intense interest in vitamin D3 as a modifying factor in the development of immune responses. However, the effects of DVD deficiency on immune function remains unknown. Thus, a model of DVD deficiency has been developed in Sprague-Dawley rats. Briefly, female rats were maintained on a vitamin D3 deficient diet prior to and during gestation. At birth dams were returned to a vitamin D3 replete diet. Post-weaning their offspring, the DVD-deficient rats, were maintained on a vitamin D3 replete diet. Therefore, this model represents a transient, prenatal vitamin D3 deficiency. A number of structural and cellular changes have been described in the DVD-deficient rat brain, including ventriculomegaly, decreased growth factor expression, and increased rates of mitosis. These changes are correlated with altered adult behaviour in the DVD-deficient rat, including a locomotor sensitivity to novelty. This thesis will focus on extending these findings and characterising immune function in the DVD-deficient rat. Vitamin D3 can affect cellular differentiation and is anti-proliferative and pro-apoptotic in many tissues including the brain. The effect of DVD deficiency on brain development has been restricted to neuronal cells in vivo and in vitro. However, the effect of this exposure on glial cell maturation and phenotype was unknown. The experiments reported in this thesis demonstrated that primary cortical glial cell cultures from DVD-deficient rat neonates displayed a similar phenotype and maturational status compared with cells from control rats. Learning and memory was examined in this model by exploring the phenomenon of latent inhibition. DVD-deficient rats displayed normal latent inhibition, however, they exhibited a subtle performance acquisition deficit during the early stages of the conditioned avoidance learning task. Extended handling and pre-exposure were able to ameliorate this deficit, though with this treatment normal latent inhibition was also abolished in both control and DVD-deficient rats. Ultrasonic vocalization and nociceptive threshold testing confirmed that alterations in peripheral sensation could not explain this performance acquisition deficit. The results suggested that anxiety or attentional mechanisms may have contributed to this rate of learning deficit. Finally, as vitamin D3 is a powerful immunoregulator, there is the potential for a transient DVD deficiency to induce a persistent alteration in the development and function of the immune system. This hypothesis was supported by findings that showed DVD deficiency resulted in a primed immune system, as indicated by an enlarged spleen, thymus and peripheral lymph tissue as well as increased pro-inflammatory cytokine production in response to an in vitro stimulation. However, these findings did not lead to an alteration in cell mediated immune response in vivo. The results from the research reported in this thesis indicate that a transient, prenatal vitamin D3 deficiency had a subtle yet significant effect on the immune system and behaviour of the adult rat. These findings add further weight to the body of evidence that link prenatal vitamin D3 status to various adverse health outcomes. The DVD-deficient rat model is an integral step in understanding prenatal vitamin D3 deficiency as a potential environment risk factor in the development of immune and psychiatric disorders.
| Identifer | oai:union.ndltd.org:ADTP/254002 |
| Creators | Louise Harvey |
| Source Sets | Australiasian Digital Theses Program |
| Detected Language | English |
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