Neural circuit formation and information processing in the brain require precise control of the development and remodeling of actin-rich dendritic spines and the excitatory synapses they house. Dynamic regulation of AMPA- and NMDA-type glutamate receptors, which mediate fast excitatory synaptic transmission and synaptic plasticity, respectively, is a key aspect of this control. Synaptic pathology characterizes many brain disorders including intellectual disabilities, autism, bipolar disorder, depression, and Alzheimer's disease. Thus, uncovering the mechanisms that control spine/synapse development and glutamate receptor regulation will provide critical insights into brain function and disease. Rho GTPases are master regulators of spine/synapse development and remodeling. Rac1 promotes spine/synapse formation, growth and maintenance, whereas RhoA suppresses these processes; both also play pivotal roles in synaptic plasticity. Proper function of Rho GTPases requires exquisite spatiotemporal control and disruption of this regulation results in numerous brain disorders. Rho GTPases are activated by guanine nucleotide exchange factors (GEFs) and inhibited by GTPase activating proteins (GAPs). However, remarkably little is known about how these GEFs/GAPs shape spatiotemporal Rac1/RhoA activation patterns and effector responses that direct the formation of neural circuits in brain. We identified the Rac1-GEF Tiam1 as a critical regulator of dendrite, spine, and synapse de- velopment, demonstrating that it couples synaptic receptors to Rac1 activation and actin cytoskeletal remodeling in cultured hippocampal neurons. In the last grant cycle, we made the surprising discovery that Tiam1 binds to the Rac1-GAP/RhoA-GEF Bcr and that this GEF/GAP complex is required to precisely regulate synaptic Rac1 signaling and excitatory synapse formation. Bcr is linked to bipolar disorder and learning and behavioral deficits, whereas altered Tiam1 expression is seen in patients with depression and Down syndrome. We hypothesize that Tiam1/Bcr cooperate to control the activation dynamics and signaling specificity of Rho GTPases, which is required in vivo for proper spine/synapse development, NMDAR trafficking/function, learning, and mood regulation. To test this, we propose to: (1) identify the roles of Tiam1 and closely related Tiam2 in shaping spine/synapse development in vivo and the specific pathways that mediate their effects; and (2) elucidate the mechanisms by which Tiam1/Bcr control NMDARs in synaptic plasticity, learning and mood regulation. We will use a multidisciplinary approach involving mouse genetics, time-lapse live-cell and in vivo two-photon imaging, Frster Resonance Energy Transfer (FRET), electrophysiology, biochemistry, molecular and cellular biology, and behavioral analyses. Our findings will elucidate key mechanisms that control Rho GTPase-dependent synaptic development/plasticity, providing critical insight into normal brain development, the connection between altered Rho GTPase signaling and cognitive/mood disorders, and potential treatments.
NARRARIVE We propose to investigate the mechanisms that regulate how connections in the brain (synapses) form during development and how they remodel during processes like learning and memory. We will study a fundamental signaling transduction pathway that is linked to a wide variety of human brain disorders including intellectual disabilities, autism spectrum disorder, bipolar disorder, depression, and Alzheimer's disease. Our study will elucidate key mechanisms that control synapse development and plasticity, which will provide critical insight into brain development, enhance our understanding of the causes of cognitive and mood disorders, and potentially identify new therapeutic targets for the treatment of these diseases
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