Synapses are highly organized cellular structures that underlie neuronal communication. The formation of synapses is promoted by trans-synaptic interactions, and the adhesive complexes spanning the cleft are now understood to have instructive roles during synapse development. Our recent progress has shown that the immunoglobulin adhesion protein SynCAM 1 induces and maintains excitatory synapses, and that it contributes to shaping the synaptic cleft. The long-term goal of our research program is to define how trans- synaptic interactions organize synapse formation and maturation. The central hypothesis underlying the research proposed in this application is that synaptic adhesion molecules engage select signaling pathways to control presynaptic assembly and postsynaptic maturation, and dynamically remodel the synaptic connectivity of mature neurons in an activity-dependent manner.
Three specific aims will be pursued to test this hypothesis. First, the presynaptic scaffolding and postsynaptic signaling mechanisms of SynCAM 1 will be defined. A combination of molecular and imaging approaches will be used to analyze a novel presynaptic partner, and characterize the postsynaptic regulation of small GTPases downstream of SynCAM 1. Second, the surface dynamics and activity-dependent properties of synaptic adhesion proteins will be probed.
This aim employs live single particle tracking of adhesion proteins on the surface of cultured neurons. Third, it will be analyzed how synapse-organizing proteins promote synaptic connectivity during learning. We will address this question in a transgenic mouse model that allows manipulating synaptogenesis in a neuron-select manner during memory processes.
These aims are significant because they determine how trans-synaptic interactions engage pre- and post-synaptic mechanisms to guide synapse development, and how these synapse-organizing complexes remodel synapses and control neuronal wiring. By establishing these fundamental aspects of synaptic biology, this research defines on molecular and in vivo levels how synaptogenic adhesion proteins control synapse formation and remodeling, enabling us to understand disorder-linked aberrations.

Public Health Relevance

Nerve cells communicate with each other in the brain through specialized junctions, called synapses. These junctions form in the human brain soon before birth, and changes in this process impair the wiring of the brain and can cause mental retardation. This research program is relevant to public health because it will analyze how nerve cells connect to each other in the healthy brain, allowing us to understand what steps go wrong in developmental disorders.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Wu, Da-Yu
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Yale University
Schools of Medicine
New Haven
United States
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Kuo, Yi-Chun; He, Xiaojing; Coleman, Andrew J et al. (2018) Structural analyses of FERM domain-mediated membrane localization of FARP1. Sci Rep 8:10477
Coleman, Andrew; Biederer, Thomas (2018) Open Up to Make New Contacts: Caldendrin Senses Postsynaptic Calcium Influx to Dynamically Organize Dendritic Spines. Neuron 97:994-996
Biederer, Thomas; Kaeser, Pascal S; Blanpied, Thomas A (2017) Transcellular Nanoalignment of Synaptic Function. Neuron 96:680-696
Salzberg, Yehuda; Coleman, Andrew J; Celestrin, Kevin et al. (2017) Reduced Insulin/Insulin-Like Growth Factor Receptor Signaling Mitigates Defective Dendrite Morphogenesis in Mutants of the ER Stress Sensor IRE-1. PLoS Genet 13:e1006579
Park, Kellie A; Ribic, Adema; Laage Gaupp, Fabian M et al. (2016) Excitatory Synaptic Drive and Feedforward Inhibition in the Hippocampal CA3 Circuit Are Regulated by SynCAM 1. J Neurosci 36:7464-75
Perez de Arce, Karen; Schrod, Nikolas; Metzbower, Sarah W R et al. (2015) Topographic Mapping of the Synaptic Cleft into Adhesive Nanodomains. Neuron 88:1165-1172
Ribic, Adema; Liu, Xinran; Crair, Michael C et al. (2014) Structural organization and function of mouse photoreceptor ribbon synapses involve the immunoglobulin protein synaptic cell adhesion molecule 1. J Comp Neurol 522:900-20
Cheadle, Lucas; Biederer, Thomas (2014) Activity-dependent regulation of dendritic complexity by semaphorin 3A through Farp1. J Neurosci 34:7999-8009
Giza, Joanna I; Jung, Yonwoo; Jeffrey, Rachel A et al. (2013) The synaptic adhesion molecule SynCAM 1 contributes to cocaine effects on synapse structure and psychostimulant behavior. Neuropsychopharmacology 38:628-38
Park, Kellie; Biederer, Thomas (2013) Neuronal adhesion and synapse organization in recovery after brain injury. Future Neurol 8:555-567

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