Molecular Interactions Regulating Trans-Synaptic Signaling Studied

Scientists at Korea's Daegu Gyeongbuk Institute of Science and Technology and colleagues have uncovered some of the complex molecular mechanisms involved in the formation of the brain's neural circuits. Their findings were published in The Journal of Neuroscience. 

"A comprehensive understanding of synaptogenesis is essential for designing therapeutic approaches against many devastating brain disorders," says researcher Jaewon Ko. "So it's really crucial to develop fine-tuned molecular manipulations that can target key synapse components in order to understand their roles."

Ko and his team looked at two key synaptic adhesion molecules involved in synaptogenesis. Neurexins and leukocyte common antigen-related protein tyrosine phosphatases (LAR-RPTPs) are transmembrane proteins that are located on the presynaptic sending side of a developing nerve junction. They are known to be involved in the formation and maintenance of synapses. But it has been unclear whether they cooperate with each other and how they interact with other synaptic molecules in regulating synapse organization.

To address these questions, they conducted a series of extensive experiments in rodent nerve cell cultures and then in fruit flies in which Drosophila orthologs of neurexins and LAR-RPTPs were deleted. They observed that two members of LAR-RPTPs (termed PTPσ and PTPδ) are required for neurexins to promote presynaptic differentiation. At the sending end of the developing synapse, neurexins bind to either of the two LAR-RPTPs through a distinct set of molecules depending on whether the synapse will be excitatory or inhibitory; in other words if it will send signals to activate or to turn off its receiving nerve end.

The scientists also found that PTPσ and neurexin directly interact through specific glycans, called heparan sulphates, to direct the formation of the receiving nerve end at excitatory synapses. "We believe that our findings have significance in terms of proposing a novel molecular model underlying synapse organization, and possibly have implications for understanding neural circuit architecture and brain functions," says Ko.