| Description |
Proper brain function requires billions of neurons to organize and communicate through specialized cell junctions called synapses. Synapses are fundamental units of neural circuits that ultimately control sensation, memory, intellect, and behavior. Importantly, synapses do not form randomly between neurons. Instead, neurons find specific partners and build specific kinds of synapses, a process known as synaptic specificity. The mechanisms that regulate synaptic specificity are not well understood, but it is thought that synaptic cell-adhesion molecules act as selective recognition tags that mediate contact recognition between synaptic partners. In this dissertation, I study the role of neurodevelopmental disorder-related cell adhesion molecules in synaptic specificity using the rodent hippocampal mossy fiber synaptic complex as a model system. I provide evidence that two cell-adhesion molecules, Cadherin-9 and Kirrel3, regulate the development of specific synapses arising from the single axons by coupling selective transcellular adhesion with unique signaling effects. To support this, I demonstrate that transsynaptic adhesion alone is not sufficient for Cadherin-9 mediated synapse development by comparing and contrasting it to the closely related family member N-cadherin. This divergent role is likely not due to differences in localization or binding partners. Rather, I suggest that molecule intrinsic biomechanical differences account for the specific function of Cadherin-9 in synapse development. Likewise, by studying wild-type Kirrel3 and disease-associated missense variants, I demonstrate that iv transcellular adhesion alone is not sufficient for Kirrel3 mediated synapse development. Rather Kirrel3 likely signals via unidentified partners to induce synapse formation. Despite the fact that Kirrel3 and cadherins are from very different protein families, this work is unified by three points. First, it advances our understanding of how synapse specificity is achieved by providing mechanistic evidence that transsynaptic adhesion alone is not sufficient for synapse development. Second, the study gives mechanistic details about how a single axon identifies and builds synapses with two distinct postsynaptic targets mediated by Kirrel3 and Cadherin-9. Finally, this research has significant potential to impact human health because variations in Kirrel3 and Cadherin genes are associated with neurological disorders that may be explained synaptic specificity defects. |
