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

项目总结 树枝状结构在其宏观结构(乔木)上表现出巨大的多样性，这规定了一种 神经元到电路及其计算特性和微观结构(树突棘)，它动态地 支持和塑造突触功能。必须协调乔木和脊椎/突触的发育才能形成 有功能的树突。尽管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，还需要其他机制。在这个提案中，我们将检验这一假设 黏附G蛋白偶联受体(A-GPCR)脑特异性血管生成抑制因子1(BAI1/ ADGRB1)通过差异激活多个 信号通路。这一假设是基于我们公布的初步数据显示：(I)BAI1 通过与Rho家族小GTP酶RhoA偶联的新途径介导树枝的生长停滞； (Ii)BAI1通过Rho家族Small促进皮层和海马神经元兴奋性突触发生 GTPase rac1和跨突触信号；以及(Iii)BAI1不同程度地影响AN树突状细胞的发育。 以及改变BAI1构型对下游具有年龄依赖性影响 信号通路。我们提出了一种多学科的方法来定义BAI A-GPCRs在调节中的作用 并利用体内和培养的神经元，协调树突和脊椎/突触的发育， 模型、分子置换、荧光记者活体成像、混合培养分析、生物化学 和电生理学。我们正在定义的通路包括与治疗耐药有关的蛋白质 双相情感障碍(BCR)、自闭症谱系障碍(神经连接蛋白-1和IRSP53)和精神分裂症(BAI3)。因此， 这一建议的成功不仅将在树枝晶发育和研究方面取得实质性进展 突触发生，但也测试了一个关于这些过程协调的新的和强有力的假说 并针对普遍存在的人类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.