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.
We propose to investigate the mechanisms that regulate how neurons obtain their characteristic shapes, form connections in the brain (synapses), and how these processes are coordinated. We will study cell surface receptors that regulate a fundamental signaling transduction pathway linked to a wide variety of human brain disorders including bipolar disorder, intellectual disabilities, autism spectrum disorder, depression, and Alzheimer's disease. Our study will elucidate key mechanisms that control dendrite and synapse development, providing critical insight into brain development, enhancing our understanding of the causes of cognitive and mood disorders, and identifying new therapeutic targets for the treatment of these diseases.
|Tu, Yen-Kuei; Duman, Joseph G; Tolias, Kimberley F (2018) The Adhesion-GPCR BAI1 Promotes Excitatory Synaptogenesis by Coordinating Bidirectional Trans-synaptic Signaling. J Neurosci 38:8388-8406|