Synaptic Cell Adhesion And Functional Architecture Of CNS Synapses
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Synapses are specialized intercellular junctions through which neurons communicate. The two sides of a synapse are held together with adhesion molecules. We investigated the role of synaptic adhesion molecules neuroligins, neurexins, SynCAM and dystroglycan using overexpression and knock-out mice analysis approaches. We showed that neuroligins mediate validation of synapses in an activity dependent manner and different isoforms of neuroligins mediate different types of synapse validation. We also showed that binding partners of neuroligins, i.e. neurexins, have a cell autonomous effect on inhibitory synapses, independent of neuroligins. Analysis of dystroglycans failed to reveal a significant phenotype in dissociated cultures, whereas SynCAM had a robust synapse inducing role in developing networks. Furthermore we have shown that this effect of SynCAM is mediated through its cytoplasmic interactions. We further investigated cytoplasmic downstream effectors of neurexins and SynCAM by analyzing CASK and Mint proteins using knock-out approaches. We have shown that both CASK and Mints are essential for survival and synaptic function. Our results indicate that synaptic cell adhesion molecules are not merely passive structural elements but actively participate in information transfer and signaling between neurons by interacting with each other and with their intracellular effectors. We have also investigated homeostatic properties of vesicle recycling and we have demonstrated that activity levels of a neuronal network determines the pathways through which synapses replenish the neurotransmitter vesicles during high frequency stimulation. Finally, we explored the relationship between evoked and spontaneous vesicle fusion and their postsynaptic targets using NMDA receptors. We uncovered previously unexpected segregation of receptor pools that respond to spontaneous or evoked vesicle fusion events. Our experiments also revealed that synaptic cleft is not a mere empty space but rather a complex structure filled with various elements can effect diffusion of neurotransmitter and hence information transfer between neurons.