The role of the clustered protocadherins in neural circuit formation and implications for neurodevelopmental disorders

项目摘要 大约800亿个人类神经元之间的功能电路连接着数万亿个突触， 人类的大脑必须在发育过程中建立。由于无法组织适当的神经回路 与自闭症和神经精神疾病等神经发育障碍有关。在开发过程中， 单个神经元延伸高度分支的神经突，以最小的 重叠此外，一些神经元亚型，如多巴胺能和多巴胺能神经元，必须 在整个大脑的感受野，以确保他们的神经突不交叉或与姐妹或 邻近的神经突或相同类型的其他神经元。这些神经元细胞类型的正确布线是必需的 5-羟色胺和多巴胺在大脑中的生理分布。 在哺乳动物中，一个高度多样化的细胞表面嗜同性蛋白家族，即成簇的原钙粘蛋白 （cPcdh）为每个神经元提供正常神经回路组装所需的唯一细胞特异性身份。的 原钙粘蛋白基因簇包括三个不同的基因簇，命名为cadherin、cadherin和cadherin， 我们实验室的研究表明，需要Pcdh β基因簇（Pcdh β c2）中的单个基因 正常的多巴胺能神经连接。整个Pcdh β基因簇或Pcdh β c2单独缺失会导致 能神经元的聚集和交叉（平铺缺陷），以及行为改变（抑郁和 增强的恐惧反应）。 这些发现为确定单个cPCDH蛋白在特定的细胞中的作用提供了重大进展。 神经元亚型;然而，在其他神经元亚型中特异性cPcdh亚型的排他性表达的作用 亚型和用于执行自我回避和平铺的机制仍然知之甚少。这里我们 我建议通过研究cPcdh基因簇在连接中的作用来解决这些理解上的差距。 多巴胺能神经元和小鼠的行为。在目标1中，我们将调查cPcdh的转录景观 在小鼠中脑多巴胺能神经元中的亚型。在目的2中，我们将研究Pcdhβ簇的作用 多巴胺能神经连接、多巴胺释放、奖励预测和新奇行为。在目标3中，我们 研究PCDHβ蛋白的作用机制，建立适当的DAN组织。总之，这些新 方向应该提供新的见解的分子逻辑神经回路形成的基础， 对神经发育和神经精神障碍的影响。

PROJECT SUMMARY Functional circuits between the approximately 80 billion human neurons connecting trillions of synapses in the human brain must be established during development. Failure to organize proper neural circuits has been linked to neurodevelopmental disorders such as autism and neuropsychiatric diseases. During development, individual neurons extend highly branched neurites that innervate the surrounding territory with minimal overlap. Moreover, some neuronal subtypes, such as serotonergic and dopaminergic neurons, must tile throughout receptive fields in the brain to ensure that their neurites do not cross over or clump with sister or neighboring neurites or other neurons of the same type. Proper wiring of these neuronal cell types is required for the physiological distribution of serotonin and dopamine in the brain. In mammals, a family of highly diverse cell-surface homophilic proteins, the clustered protocadherins (cPcdh), provides each neuron a unique cell-specific identity required for normal neural circuit assembly. The protocadherin gene cluster encompasses three distinct gene clusters, designated ,  and and previous studies from our laboratory demonstrated that a single gene in the Pcdh gene cluster (Pcdhc2) is required for normal serotonergic wiring in mice. Deletion of the entire Pcdh gene cluster or Pcdhc2 alone led to clumping and crossing of serotonergic neurons (a tiling defect), and altered behavior (depression and enhanced fear response). These findings provided significant advances in defining a role for individual cPCDH proteins in specific neuronal subtypes; however, a role for the exclusive expression of specific cPcdh isoforms in other neuronal subtypes and the mechanisms used to execute self-avoidance and tiling remain poorly understood. Here, we propose to address these gaps in understanding by studying the role of the cPcdh gene cluster in the wiring of dopaminergic neurons and behavior in mice. In Aim 1, we will survey the transcriptional landscape of cPcdh isoforms across midbrain dopaminergic neurons in mice. In Aim 2, we will investigate the role of Pcdhβ cluster on dopaminergic wiring, dopamine release and reward prediction and novelty behaviors. In Aim 3, we will examine the mechanism by which PCDHβ proteins, establish proper DAN organization. Together, these new directions should provide novel insights into the molecular logic underlying neural circuit formation and have implications for neurodevelopmental and neuropsychiatric disorders.