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, which is a risk factor for autism and intellectual disability and other mental illnesses, is selectively required for formation of a specific type of hippocampal synapse that connects DG neurons to GABA neurons. 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 how it functions. Through a series of in vitro assays, our new preliminary data suggests that Kirrel3 binds other Kirrel3 molecules in cis and trans, functions directly in pre- and post-synapse formation, and requires yet to be identified neuron-specific binding partner(s). In the hippocampus, Kirrel3 is only expressed by DG and GABA neuron. Thus, we will test the central hypothesis that homophilic, trans-cellular Kirrel3 interactions nucleate DG-to-GABA synapses by sending bi-directional signals to actively recruit pre- and post-synaptic proteins.
In Aim 1, we will determine if Kirrel3 function requires trans-cellular binding in vivo by determining precisely where, when, and how much Kirrel3 is required to build hippocampal DG-to-GABA synapses.
In Aim 2, we will define the role of Kirrel3 in adhesion versus synapse formation and identify binding partners and downstream signaling mechanisms mediated by Kirrel3. Kirrel3 provides a new approach to identify the still elusive mechanisms of target-specific synapse formation and, given its links to disease, our results will provide basic insight to the etiology of cognitive and mental illnesses.
Kirrel3 is necessary to form specific types of neural connections called synapses and genetic changes in Kirrel3 are emerging as a risk factor for autism and intellectual disability and other mental illnesses. Therefore, our research to determine precisely how Kirrel3 regulates synapse form and function is expected to contribute to our understanding of cellular defects underlying brain diseases and new ways to treat them.