Modeling 5-HT-absorbing neurons in neuropathology of autism

描述（由申请人提供）：自闭症是一种出生后神经发育障碍，诊断基于沟通，社会互动和刻板行为模式的核心缺陷。尸检研究揭示了前额叶皮层、杏仁核和海马体的解剖组织和轴突和树突分支的改变，导致了自闭症是一种突触连接疾病的概念，关键神经元回路的破坏强调了行为和认知缺陷。基于家族的关联研究表明，5-羟色胺再摄取转运蛋白（SERT）基因SLC 6A 4的表达/功能降低与自闭症之间存在联系。与SERT功能降低扰乱自闭症神经元回路的想法一致，SERT敲除小鼠表现出躯体感觉图的缺陷，边缘下区和杏仁核中锥体细胞树突形态的改变以及增强的焦虑特征。然而，选择性5-羟色胺再摄取转运体抑制剂（SSRIs）被发现对改善自闭症患者的重复和强迫行为是有用的，这是一个悖论。克服这一悖论将有助于我们理解自闭症的神经病理生理机制，并设计合理的治疗方法。要了解SERT缺陷在自闭症神经病理生理学中的作用，关键是要阐明原发性脑损伤发生在哪个发育阶段以及机制是什么。本提案的目的是研究如何在新生儿阶段的一组特定的神经元- 5-HT吸收神经元的SERT的瞬时表达调节特定脑区的神经元突触模式，以及是否消融这种SERT功能将导致行为缺陷自闭症，利用我们独特的条件性SERT基因敲除小鼠。我们最近发现，通过SERT吸收突触外5-HT但不合成5-HT的5-HT吸收神经元控制C.优雅我们证明了在5-HT吸收神经元中SERT的转基因表达是必要的，并且足以纠正SERT无效蠕虫的夸张行为。值得注意的是，5-HT吸收神经元在新生啮齿动物和人脑中短暂存在。在小鼠中，5-HT吸收神经元存在于初级感觉区域，包括体感、视觉和听觉皮质、海马和前脑部位，包括边缘下区。所提出的实验将确定SERT的5-HT吸收神经元特异性失活对躯体感觉地图模式、额叶皮层和杏仁核中的轴突和树突分支以及压力和社会行为的影响。我们将评估消融这种短暂的SERT功能是否会导致大脑解剖和行为的持久改变，以及这些影响是否存在性别偏见。这些结果将为5-HT神经传递的基本机制提供新的见解，并阐明SERT如何在正确的时间在正确的细胞中发挥作用，以调节自闭症所涉及的大脑解剖结构和行为回路。

DESCRIPTION (provided by applicant): Autism is a postnatal neurodevelopmental disorder diagnosed based on a core of deficits in communication, social interaction, and stereotypic patterns of behavior. Postmortem studies revealed alterations in anatomical organizations and axonal and dendritic arborization in the prefrontal cortex, amygdala and hippocampus, leading to the notion that autism is a disease of synaptic connectivity and that disruption of critical neuronal circuitry underscores the behavioral and cognitive deficits. Family based association studies indicated a link between reduced expression/function of serotonin reuptake transporter (SERT) gene SLC6A4 and autism. Consistent with the idea that reduced SERT function perturbs neuronal circuitry underlying autism, SERT knockout mice exhibit deficits in somatosensory maps, alterations in pyramidal cell dendritic morphology in the infralimbic area and amygdala and enhanced anxiety traits. However, Selective Serotonin Reuptake Transporter Inhibitors (SSRIs) are found to be useful for improving repetitive and compulsive behavior of autistic patients, posting a paradox. Overcoming this paradox will help our understanding the mechanisms underlying the neuropathophysiology of autism and designing rational treatments. To understand the role of SERT deficiency in neuropathophysiology of autism, it is critical to elucidate at which developmental stage do the primary brain lesions occur and what are the mechanisms. The goal of this proposal is to investigate how a transient expression of SERT in a particular set of neurons -- 5-HT-absorbing neurons, during the neonatal stage regulates neuronal synaptic patterning in particular brain regions and whether ablating this SERT function would lead to behavioral deficits seen in autism, by making use of our unique conditional SERT knockout mouse. This proposal is inspired by our recent discovery that 5-HT-absorbing neurons, which absorb extra-synaptic 5-HT via SERT but do not synthesize 5-HT, control stress behavior in C. elegans. We demonstrated that transgenic expression of SERT in the 5-HT-absorbing neurons is necessary and sufficient to correct exaggerated behavior of SERT-null worms. Remarkably, 5-HT-absorbing neurons are present transiently in the neonatal rodent and human brains. In mouse, 5-HT-absorbing neurons are present in primary sensory areas including somatosensory, visual and auditory cortices, the hippocampus, and forebrain sites including the infralimbic area. The proposed experiments will determine the effects of 5-HT-absorbing neuron- specific inactivation of SERT on somatosensory map patterning, axonal and dendritic arborization in the frontal cortex and amygdala, and stress and social behavior. We will assess whether ablating this transient SERT function would lead to lasting alterations in brain anatomy and behavior, and if those effects are sex biased. The results will provide new insights into fundamental mechanisms of 5-HT neurotransmission and illuminate how SERT acts in right cells at right time to regulate brain anatomy and behavioral circuits implicated in autism.