A MOUSE MODEL FOR AUTISM: POSTNATAL SEROTONERGIC EFFECTS

自闭症小鼠模型：产后血清素效应

• 批准号: 6670962
• 负责人: Mary E Blue
• 金额: $ 26.31万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6670962
• 关键词: AMPA receptors; NMDA receptors; attention; autism; autoradiography; brain morphology; cerebral cortex; cognition; cooperative study; developmental neurobiology; disease /disorder model; fluoxetine; high performance liquid chromatography; hippocampus; hydroxyindoleacetate; immunocytochemistry; laboratory mouse; mental disorder chemotherapy; neural transmission; newborn animals; nonhuman therapy evaluation; psychomotor function; receptor expression; sensory feedback; serotonin; serotonin receptor

The serotonergic (5-HT) neurotransmitter system plays a major role in modulating postnatal development of the brain, including neuronal differentiation, synaptogenesis and developmental plasticity. Perturbations in 5-HT neurotransmission affect neuronal development and plasticity. Studies in rodents and humans indicate that markers for serotonin neurotransmission are enhanced in the immature brain compared to adults. However PET studies show that the early rise in serotonin metabolism is blunted in some children with autism. Clinical trials with drugs targeting serotonin neurotransmission demonstrate ameliorative potential for several debilitating autistic deficits, e.g., self-injury; stereotypy; mood disorders; cognitive parameters. Proposed experiments will determine in an animal model that involves neonatal 5-HT depletions whether selected structural and pharmacological changes in neocortex resemble those observed in autistic patients. Consistent with recent findings of increases in cortical volume in autistic brains, we have recently shown that cortical width expands when 5-HT afferents to rodent cortex are depleted at birth with the 5-HT neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). As in autism, specific changes vary by sex, cortical region and hemisphere. These neonatal 5-HT depletions also precipitate behavioral changes, indicative of altered attentional processes. This has lead us to the hypotheses that the cerebral cortical alterations observed in autism, are 1) the result of altered development of the 5-HT innervation cortex and 2) that cognitive changes and disturbances in sensory processing are the consequence of altered cortical development. Our specific aims are 1) to determine the time course of altered 5-HT innervation and function after neonatal 5,7 DHT injections into the medial forebrain bundle and 2) to characterize the effect of neonatal 5-HT depletion on development of thalamocortical connectivity and receptor ontogeny, 3) to characterize changes in social, affective and cognitive behaviors in mice with neonatal serotonergic depletions and to compare these to behavioral changes in mice with early prenatal serotonergic hypoinnervation and 4) to determine whether cortical volume is altered after neonatal 5-HT depletion and whether any alterations are due to changes in white or gray matter.

血清素能（5-HT）神经递质系统在调节大脑产后发育（包括神经元分化，突触发生和发育可塑性）中起着重要作用。 5-HT神经传递的扰动会影响神经元的发育和可塑性。对啮齿动物和人类的研究表明，与成年人相比，未成熟大脑中5-羟色胺神经传递的标志物得到了增强。然而，宠物研究表明，一些自闭症儿童的羟色胺代谢的早期升高被削弱。针对5-羟色胺神经传递的药物的临床试验表明，几种虚弱的自闭症缺陷，例如自我伤害表现出了改善的潜力；刻板印象；情绪障碍；认知参数。提出的实验将在涉及新生儿5-HT耗竭的动物模型中确定，新皮层的结构和药理变化是否类似于自闭症患者中观察到的结构和药理变化。与最新的自闭症大脑皮质体积增加的发现相一致，我们最近表明，当5-HT神经毒素5,7-7-二羟基毒素tryptamine（5,7-DHT）出生时，5-HT传入到啮齿动物皮质的传入时，皮质宽度会扩大。与自闭症一样，特定的变化因性别，皮质区域和半球而异。这些新生儿5-HT耗竭也会导致行为变化，这表明注意力变化。这使我们提出了以下假设：自闭症中观察到的脑皮质改变是1）5-HT神经皮质的发育改变的结果和2）认知变化和 感觉处理中的干扰是皮质发育改变的结果。我们的具体目的是1）确定新生儿5,7 DHT后5-HT支配和功能发生变化的时间过程，向内侧前脑束和2）表征新生儿5-HT耗竭对丘脑皮层连接性和受体的发展的影响，以与社交性行为的特征性行为变化，以改变丘脑皮层连接性和受体的影响。耗尽并将其与早期产前的小鼠的行为改变进行比较 血清素能性低作用和4）确定新生儿5-HT耗竭后皮质体积是否改变，以及是否由于白色或灰质的变化而造成的任何改变。