Molecular mechanisms of target-specific synapse formation

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PROJECT SUMMARY/ABSTRACT Proper brain function requires that neurons make specific types of synapses with specific types of target neurons. Defects in this process of synapse specficity can alter brain activity and may underlie many types of mental illnesses but we know little about the mechanisms by which synapse specificity develops. We recently discovered that the cell adhesion molecule Kirrel3 is selectively required to form a specific type of synapse that connects DG neurons to GABA neurons in the hippocampus. This synapse provides feed-forward inhibition to CA3 and Kirrel3 null mice have significantly elevated CA3 neuron activity. This established Kirrel3 as a functionally relevant target-specific synaptogenic molecule but we still do not know the mechanism of Kirrel3 function. Through a series of in vitro assays, our new preliminary data suggests that Kirrel3 binds other Kirrel3 molecules in cis and trans, directs the assembly of pre- and post-synapses, and its function requires yet to be identified neuronal molecules. Here, we will test the central hypothesis that homophilic, trans-cellular Kirrel3 interactions nucleate DG-to-GABA synapses in vivo by recruiting synaptic proteins to axon-dendrite contact points. In Aim 1, we will determine precisely where, when, and how much Kirrel3 is required to build hippocampal DG-to-GABA synapses in vivo. In Aim 2, we will identify Kirrel3 signaling mechanisms by defining properties controlling the differential subcellular localization of Kirrel3 isoforms and identifing Kirrel3 interacting proteins. Together, the study of Kirrel3 provides a new approach to identify the still elusive mechanisms of target-specific synapse formation and a framework for understanding how changes in synapse specificity impact hippocampal circuit function, which plays a central role in learning and memory processes.