The Developmental vitamin D model (DVD) as an animal model for schizophrenia

大多数澳大利亚人有机会享受阳光带来的自然好处，但许多澳大利亚人缺乏维生素D。我们已经证明，即使在所谓的阳光州昆士兰，隆冬时节的维生素D水平也低于世界卫生组织的推荐水平。我们正在探索低母亲维生素D作为对全球普遍现象的生物学解释，即在一年中较冷的几个月出生时患有精神分裂症的患者的发病率增加7%-10%。精神分裂症是一种发育性疾病，出现在青春期，影响着世界上约1%的人口。到目前为止，我们已经发现，怀孕期间血液维生素D水平较低或维生素D摄入量不足的母亲所生的子女患精神分裂症的数量增加。因此，早期迹象似乎很有希望，但显然需要更多的研究来证实这一观点。我们在动物身上的研究表明，通过限制怀孕大鼠的维生素D摄入量，新生儿的大脑发育不同。最值得注意的是侧脑室容量增加，这是精神分裂症患者的关键解剖学发现。当这些动物成年后，侧脑室的增加持续存在。此外，当我们研究这些动物的行为时，我们发现学习和记忆方面的缺陷与许多精神分裂症患者的情况相似。此外，当我们将这些动物暴露于诱发精神错乱的药物或阻断患者精神错乱的药物时，我们发现在子宫中被剥夺这种维生素的动物，特别是在运动中，敏感度更高。这些行为发现与最好的精神分裂症动物模型是一致的。在机制水平上，它们表明大脑中的两种主要神经递质--多巴胺和谷氨酸--存在异常，这两种递质一直与这种疾病有关。本申请中概述的实验将试图为这些改变的行为建立神经化学基础。

Most Australians have the opportunity to enjoy the natural benefits of sunlight, however many Australians lack vitamin D. We have shown that even in Queensland, the so-called Sunshine State, vitamin D levels in the middle of winter are below World Health Organisation recommended levels. We are exploring low maternal vitamin D as a biological explanation for the universal phenomena worldwide of a 7-10% increase in the incidence of patients born with schizophrenia in the colder months of the year. Schizophrenia is a developmental disease that presents in adolescence and affects about 1% of the world's population. To date we have shown increased amounts of schizophrenia in offspring from mothers that had low blood vitamin D levels during pregnancy or who had inadequate vitamin D intake. Early signs therefore appear promising but obviously more research is required to confirm this idea. Our studies in animals have revealed that by restricting vitamin D intake in pregnant rats, newborns have brains that develop differently. Most notably lateral ventricle volume is increased, a key anatomical finding in patients with schizophrenia. When these animals become adults the increase in lateral ventricles persists. Also when we explore the behaviour of these animals we find a deficit in learning and memory similar to that seen in many schizophrenic patients. Furthermore when we expose these animals to agents that induce psychosis or agents that block psychosis in patients we see a heightened sensitivity in animals that were deprived of this vitamin in utero particularly in locomotion. These behavioural findings are consistent with the best animal models for schizophrenia. At a mechanistic level they indicate an abnormality in the two major neurotransmitters in the brain that have been consistently linked with this disease, dopamine and glutamate. The experiments outlined in this application will attempt to establish the neurochemical basis for these altered behaviours.