A MOUSE MODEL FOR AUTISM: POSTNATAL SEROTONERGIC EFFECTS

5-羟色胺能神经递质系统在脑的生后发育中起着重要的调节作用，包括神经元分化、突触发生和发育可塑性。5-HT神经传递的扰动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，未成熟大脑中的5-羟色胺神经传递标记物增强。然而，PET研究表明，在一些自闭症儿童中，血清素代谢的早期上升是迟钝的。靶向5-羟色胺神经传递的药物的临床试验证明了几种使人衰弱的自闭症缺陷的改善潜力，例如，自伤;刻板;情绪障碍;认知参数。拟议的实验将确定在一个动物模型，涉及新生儿5-羟色胺耗竭是否选定的结构和药理学的变化，在新皮层类似于自闭症患者中观察到的。与最近发现的自闭症患者大脑皮质体积增加相一致，我们最近发现，当5-HT神经毒素5，7-二羟色胺（5，7-DHT）在出生时耗尽啮齿动物皮质的5-HT传入时，皮质宽度扩大。与自闭症一样，具体的变化因性别、皮质区域和半球而异。这些新生儿5-羟色胺消耗也会引起行为变化，表明注意力过程改变。这导致我们假设在自闭症中观察到的大脑皮层改变是1）5-HT神经支配皮层发育改变的结果，以及2）认知改变和 感觉处理的障碍是皮层发育改变的结果。我们的具体目标是：1）确定新生儿5，7-二氢睾酮注射到内侧前脑束后5-HT神经支配和功能改变的时间过程; 2）表征新生儿5-HT耗竭对丘脑皮质连接和受体个体发育发育的影响; 3）表征社会，在新生儿肾上腺素能耗竭小鼠中的情感和认知行为，并将这些与早期产前 4）确定新生儿5-HT耗竭后皮质体积是否改变，以及任何改变是否是由于白色或灰质的变化。

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.