Modeling early cortical serotonergic deficits in autism
Modeling early cortical serotonergic deficits in autism
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DOI：
10.1016/j.bbr.2006.08.026
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发表时间：
2007-01-10
影响因子：
2.7
通讯作者：
Hohmann, Christine F.
中科院分区：
文献类型：
--
作者：
Boylan, Carolyn B.;Blue, Mary E.;Hohmann, Christine F.
自闭症是一种大脑发育障碍，其特征是社会交往、语言和行为方面的缺陷。脑成像研究表明，增加大脑皮质体积和微观和宏观神经解剖学的变化，儿童与这种疾病。前脑多巴胺能功能的改变可能是自闭症的神经解剖学和行为特征的基础。5-羟色胺参与神经元的生长和可塑性，这些作用可能是通过多巴胺能和多巴胺能受体介导的。很少有自闭症的动物模型被描述为既复制病因学又复制病理生理学。我们在这里报告一个选择性5-羟色胺（5-HT）耗竭模型，这种疾病的新生小鼠，模仿神经化学和结构的变化，在皮层，此外，显示行为表型与自闭症一致。新生的雄性和雌性小鼠前脑5-HT耗竭的注射神经毒素，5，7-二羟色胺（5，7-DHT），到双侧内侧前脑束（mfb）。这些动物成年后的行为测试显示，在社会，感觉和刻板行为的变化。病变小鼠表现出显着增加皮质宽度。5-羟色胺免疫细胞化学显示，一个戏剧性的持久耗尽5-羟色胺纤维在大脑皮层，直到出生后（PND）60。放射自显影结合高亲和力5-HT转运体显着，但短暂减少大脑皮层的5，7-DHT耗尽小鼠。在PND 15，AMPA谷氨酸受体结合减少。我们推测，增加大脑皮层体积和感觉运动，认知和社会缺陷中观察到的5-HT耗尽的动物和自闭症患者，可能是由于及时轴突修剪关键大脑皮层区域的缺陷。(c)2006 Elsevier B. V.保留所有权利。
Autism is a developmental brain disorder characterized by deficits in social interaction, language and behavior. Brain imaging studies demonstrate increased cerebral cortical volumes and micro- and macro-scopic neuroanatomic changes in children with this disorder. Alterations in forebrain serotonergic function may underlie the neuroanatomic and behavioral features of autism. Serotonin is involved in neuronal growth and plasticity and these actions are likely mediated via serotonergic and glutamatergic receptors. Few animal models of autism have been described that replicate both etiology and pathophysiology. We report here on a selective serotonin (5-HT) depletion model of this disorder in neonatal mice that mimics neurochemical and structural changes in cortex and, in addition, displays a behavioral phenotype consistent with autism. Newborn male and female mice were depleted of forebrain 5-HT with injections of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the bilateral medial forebrain bundle (mfb). Behavioral testing of these animals as adults revealed alterations in social, sensory and stereotypic behaviors. Lesioned mice showed significantly increased cortical width. Serotonin immunocytochemistry showed a dramatic long-lasting depletion of 5-HT containing fibers in cerebral cortex until postnatal day (PND) 60. Autoradiographic binding to high affinity 5-HT transporters was significantly but transiently reduced in cerebral cortex of 5,7-DHT-depleted mice. AMPA glutamate receptor binding was decreased at PND 15. We hypothesize that increased cerebral cortical volume and sensorimotor, cognitive and social deficits observed in both 5-HT-depleted animals and in individuals with autism, may be the result of deficiencies in timely axonal pruning to key cerebral cortical areas. (c) 2006 Elsevier B.V. All rights reserved.