Prostaglandins and Cerebellum Development

描述(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与遗传易感性汇合，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。这项提案探索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，并在根本不存在的地方制造脆弱性。胎儿或早期的炎症大大增加了患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(S)和敏感期仍不清楚。小脑的病理经常与这两种疾病相关，但尚未考虑到炎症对这一脑区的影响。性别也是一个主要的风险因素，男性患自闭症或自闭症(ASD)的风险几乎是自闭症或自闭症(ASD)的四倍，而且更早发病，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。利用实验室大鼠，我们提出了一个新的概念，即受限敏感期的炎症会导致前列腺素E2(PGE2)的过量，PGE2是一种促炎分子，可以刺激小脑内局部的芳香酶活性和雌二醇的合成。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，接触抗炎药物，如非甾体抗炎药或醋氨酚，会产生相反的效果，导致旺盛的树突状突起。最终，小脑正常发育过程的中断会导致青少年行为的变化，如社交游戏、焦虑和躯体感觉敏感。四个特定的目标将系统地探索一系列假说通过确定：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(S)，SA#3)内源性和外源性雌二醇对小脑浦肯野细胞发育的影响和机制(S)，SA#4)在敏感期影响浦肯野细胞发育的操作是否会对被认为是自闭症或精神分裂症相关行为变化指标的行为产生后果。这些实验产生的数据将突出以前意想不到的发育性神经精神疾病、炎症期间前列腺素升高和/或经常使用的用于阻止炎症的药物的风险来源。 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相对风险的环境变量中，胎儿或早期的炎症是其中之一。小脑的病理经常与这些神经精神障碍有关。了解炎症和治疗炎症的药物如何影响发育中的小脑，将为这些精神健康障碍的起源提供重要的机械学见解。

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.