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，其起源与发育，遗传和环境有关。了解环境影响如何在特定的发育窗口期与遗传倾向融合，从而形成一个敏感期，是发现这些复杂疾病的病因和潜在治疗方法的关键。该提案探讨了特定的环境影响、炎症和治疗它的药物如何选择性地改变大脑发育，并在不存在的情况下产生脆弱性。胎儿或生命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，但炎症导致这种风险的机制和敏感期尚不清楚。小脑的病理通常与这两种疾病有关，但炎症对这一大脑区域的影响尚未被考虑。性别也是一个主要的风险因素，男性患自闭症或（ASD）的风险几乎是男性的四倍，而且精神分裂症发病较早，症状更严重。大脑中的许多性别差异是由发育性腺激素暴露决定的。利用实验大鼠，我们提出探索一个新的概念，即在限制敏感期的炎症会导致前列腺素E2 （PGE2）过量，这是一种促炎分子，可以刺激小脑内局部的芳香酶活性和雌二醇合成。过量的雌二醇通过上调GABA的合成而阻碍浦肯野神经元树突的生长。相反，暴露于抗炎药物，如非甾体抗炎药或对乙酰氨基酚，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索一系列假设，通过确定；SA#1)前列腺素调控小脑浦肯野细胞树突发育的敏感期；SA#2)前列腺素调控小脑浦肯野细胞树突发育的机制；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；在敏感时期影响浦肯野细胞发育的操作是否会对被视为自闭症或精神分裂症相关行为改变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，即炎症期间前列腺素升高和/或经常使用的旨在阻断炎症的药物。

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.