Adhesion-GPCRs: Regulators of dendritic development, synaptogenesis and mental health

项目摘要 树突在其宏观结构（乔木）中表现出巨大的多样性，这规定了 神经元到电路及其计算特性，以及微观结构（树突棘）， 支持和塑造突触功能。乔木和棘/突触的发育必须协调才能形成 功能树突虽然突触活动起着至关重要的作用，但发育的异质性 对活动的反应表明需要其他机制。在本提案中，我们将检验假设 粘附G蛋白偶联受体（A-GPCR）脑特异性血管生成抑制因子1（BAI 1/ ADGRB 1）通过多种细胞因子的差异激活来协调树突状乔木和棘的发育。 信号通路这一假设是基于我们发表的和初步的数据表明：（i）BAI 1 通过与Rho家族小GTdR RhoA偶联的新途径介导树突状乔木的生长停滞; (ii)BAI 1通过Rho家族小分子促进皮质和海马神经元的兴奋性突触发生 GTBIRac 1和跨突触信号传导;和（iii）BAI 1差异性地影响树突发育， 年龄依赖性的方式，改变BAI 1构型具有年龄依赖性的影响下游 信号通路我们提出了一种多学科的方法来定义BAI A-GPCR在调节 以及利用体内和培养的神经元、遗传学和生物学方法协调树突乔木和棘/突触发育， 模型，分子置换，荧光报告分子实时成像，混合培养测定，生物化学 和电生理学。我们正在定义的途径包括与治疗抵抗相关的蛋白质。 双相情感障碍（Bcr）、自闭症谱系障碍（神经连接素-1和IRSp 53）和精神分裂症（BAI 3）。因此，在本发明中， 这一建议的成功不仅将在枝晶发展的研究中提供材料进步， 突触发生，但也测试了一个新的和强大的假设，关于协调这些过程 为人类广泛存在的精神疾病提供新的治疗靶点。

PROJECT SUMMARY Dendrites exhibit immense diversity in their macrostructure (arbors), which stipulates the availability of a neuron to circuits and its computational properties, and microstructure (dendritic spines), which dynamically support and shape synaptic function. Arbor and spine/synapse development must be coordinated to form functional dendrites. Though synaptic activity plays a crucial role, the heterogeneity of developmental responses to activity indicates that other mechanisms are required. In this proposal, we will test the hypothesis that the adhesion G-protein coupled receptor (A-GPCR) brain-specific angiogenesis inhibitor 1 (BAI1/ ADGRB1) coordinates dendritic arbor and spine development through differential activation of multiple signaling pathways. This hypothesis is based on our published and preliminary data showing: (i) that BAI1 mediates growth arrest of dendritic arbors via a novel pathway coupling to the Rho-family small GTPase RhoA; (ii) that BAI1 promotes excitatory synaptogenesis in cortical and hippocampal neurons via the Rho-family small GTPase Rac1 and trans-synaptic signaling; and (iii) that BAI1 differentially affects dendrite development in an age-dependent manner and that altering BAI1 configuration has age-dependent effects on downstream signaling pathways. We propose a multidisciplinary approach to define the roles of BAI A-GPCRs in regulating and coordinating dendritic arbor and spine/synapse development utilizing in vivo and cultured neurons, genetic models, molecular replacement, live imaging with fluorescent reporters, mixed culture assays, biochemistry and electrophysiology. The pathways that we are defining include proteins implicated in treatment-resistant bipolar disorder (Bcr), autism spectrum disorder (neuroligin-1 and IRSp53), and schizophrenia (BAI3). Thus, success of this proposal will not only provide material advances in the study of dendrite development and synaptogenesis, but also test a novel and powerful hypothesis regarding the coordination of these processes and provide new therapeutic targets against widespread human mental diseases.