Scientists from the Daegu Gyeongbuk Insitute of Science and Technology discover a deeper understanding to the molecular mechanisms in the regulation of the brain’s nerve fibres.
Synaptogenesis is a complex molecular process that promotes the growth and development of nerve fibre ends so that it can recognize and communicate with their appropriate nerve fibre partner through molecules transmitted across specialized junctions, called synapses.
Scientists at Korea's Daegu Gyeongbuk Institute of Science and Technology (DGIST) 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 and could be relevant for developing potential treatments for neurological diseases, such as autism spectrum disorders and schizophrenia.
“A comprehensive understanding of synaptogenesis is essential for designing therapeutic approaches against many devastating brain disorders,” said DGIST neuroscientist, Professor Ko Jaewon. “It's really crucial to develop fine-tuned molecular manipulations that can target key synapse components in order to understand their roles.” Added Professor Ko
Professor Ko and his team of scientists specifically looked at two keys which are molecules involved in synaptogenesis. Neurexins and leukocyte common antigen-related protein tyrosine phosphatases (LAR-RPTPs) are transmembrane proteins that are located on the pre-synaptic 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, the scientists conducted a series of extensive experiments in rodent nerve cell cultures and then in fruit flies, where fruit fly orthologous genes of neurexins and LAR-RPTPs were deleted. The team observed that two members of LAR-RPTPs (termed PTPσ and PTPδ) are required for neurexins to promote presynaptic differentiation. At the pre-synaptic portion 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.
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,” said Professor Ko.
The team is now investigating downstream mechanisms underlying interactions of neurexins with LAR-RPTPs in vertebrate neurons, and is working to pinpoint a set of intracellular proteins involved in trans-synaptic signalling in presynaptic neurons. Further studies are essential before these findings can be translated into clinical studies.