Prostaglandins and Cerebellum Development

描述（由申请人提供）：自闭症谱系障碍（ASD）和精神分裂症是神经精神疾病，起源于发育，遗传和环境。了解环境影响如何在特定的发育窗口期与遗传易感性汇合，以创造一个敏感期，是发现这些复杂疾病的病因和潜在治疗方法的关键。这项提案探讨了一种特定的环境影响，炎症和治疗它的药物，如何选择性地改变大脑发育，并在不存在的地方创造脆弱性。在胎儿或生命早期的炎症大大增加了发展自闭症或精神分裂症的相对风险，但炎症赋予这种风险的机制和敏感期仍然未知。小脑的病理常与这两种疾病有关，但尚未考虑炎症对该脑区的影响。性别也是一个主要的风险因素，男性患自闭症或自闭症谱系障碍（ASD）的风险几乎是男性的四倍，并且精神分裂症的发病较早，症状更严重。大脑中的许多性别差异是由发育中的性腺激素暴露决定的。使用实验室大鼠，我们建议探索新的概念，炎症在有限的敏感期导致过量的前列腺素E2（PGE 2），一种促炎分子，刺激芳香酶活性和雌二醇合成局部小脑内。过量的雌二醇通过上调GABA的合成抑制浦肯野神经元树突的生长。相反，暴露于抗炎药物，如NSAID或乙酰氨基酚，有相反的效果，导致旺盛的树突发芽。最终，小脑正常发育过程的中断会导致青少年行为的改变，如社交游戏，焦虑和体感敏感性。四个具体目标将系统地探讨一系列假设，通过确定; SA#1）前列腺素调节小脑浦肯野细胞树突发育的敏感期，SA#2）前列腺素调节小脑浦肯野细胞树突发育的机制，SA#3）内源性和外源性雌二醇对小脑浦肯野细胞发育的作用和机制，以及SA#4）在敏感期影响浦肯野细胞发育的操作是否对被视为与自闭症或精神分裂症相关的行为变化指标的行为产生影响。这些实验产生的数据将突出一个以前意想不到的发育性神经精神疾病的风险来源，炎症期间的阿托兰汀升高和/或经常使用的旨在阻断炎症的药物。 公共卫生相关性：在导致自闭症、自闭症谱系障碍和精神分裂症的相对风险的环境变量中，胎儿或早期生活中的炎症是最重要的。小脑的病理常与这些神经精神疾病有关。了解炎症和治疗它的药物如何影响发育中的小脑，将为这些心理健康疾病的起源提供重要的机制见解。

DESCRIPTION (provided by applicant): Autism Spectrum Disorder (ASD) and Schizophrenia are neuropsychiatric diseases with origins in development, genetics and the environment. Understanding how environmental influences converge with genetic predispositions during specific developmental windows to create a sensitive period is the key to discovering the etiology of and potential therapeutic treatments for these complex disorders. This proposal explores how a specific environmental influence, inflammation and the medications that treat it, can selectively alter brain development and create vulnerability where none existed. Inflammation during fetal or early life substantially increases the relative risk of developing either Autism or Schizophrenia, but the mechanism(s) and sensitive periods by which inflammation confers this risk remain unknown. Pathologies of the cerebellum are frequently associated with both disorders but an effect of inflammation on this brain region has not been considered. Gender is also a major risk factor, with males at almost four times the risk of Autism or (ASD) and an earlier onset of Schizophrenia with more severe symptoms. Many sex differences in the brain are determined by developmental gonadal hormone exposure. Using the laboratory rat, we propose to explore the novel concept that inflammation during a restricted sensitive period leads to excess prostaglandin E2 (PGE2), a proinflammatory molecule that stimulates aromatase activity and estradiol synthesis locally within the cerebellum. Excessive estradiol stunts the outgrowth of Purkinje neuron dendrites by up regulating GABA synthesis. Conversely, exposure to anti-inflammatory medications such as NSAIDs or acetominophen, has the opposite effect, causing exuberant dendritic sprouting. Ultimately, disruption of the normal course of cerebellar development produces changes in juvenile behaviors such as social play, anxiety and somatosensory sensitivity. Four specific aims will systematically explore a series of hypotheses by determining; SA#1) the sensitive period for prostaglandin modulation of cerebellar Purkinje cell dendritic development, SA#2) the mechanism(s) of prostaglandin modulation of cerebellar Purkinje cell dendritic development, SA#3) the effects and mechanism(s) of endogenous and exogenous estradiol on cerebellar Purkinje cell development and SA#4) whether manipulations that impact Purkinje cell development during a sensitive period have consequences for behaviors deemed indicators of behavioral changes associated with autism or schizophrenia. The data generated by these experiments will highlight a previously unexpected source of risk for developmental neuropsychiatric disease, prostaglandins elevated during inflammation and/or the frequently used medications designed to block inflammation. PUBLIC HEALTH RELEVANCE: Among the environmental variables contributing to the relative risk of Autism, Autism Spectrum Disorder and Schizophrenia is inflammation during fetal or early life. Pathologies of the cerebellum are frequently associated with these neuropsychiatric disorders. Understanding how inflammation and the medications taken to treat it impact on the developing cerebellum will provide important mechanistic insight into the origins of these disorders of mental health.