BALTIMORE – Researchers have pinpointed a protein,intersectin,that acts as a crucial gatekeeper for communication between brain cells,a finding that could pave the way for new treatments for cognitive disorders. Experiments in genetically engineered mice revealed intersectin’s role in organizing the tiny sacs, called synaptic vesicles, that ferry messages. This process is fundamental to learning and memory.
A protein called intersectin is vital for organizing synaptic vesicles, the bubbles that transmit signals between brain cells, essential for learning and me
Brain cells communicate by sending chemical messages to neighboring neurons. This is how brain cells achieve direct communication.
Message transfer between brain cells is key to details processing, learning and forming memories.
In mammalian brains,an estimated 300 synaptic vesicles gather at each synapse,but only a fraction are deployed to send signals. Understanding how synapses select these vesicles has been a long-standing question.
“We found that these tiny bubbles have a distinct domain where they want to be,” said Dr. Shigeki Watanabe, an associate professor of cell biology at Johns Hopkins Medicine and the study’s leader. “Keeping them at particular locations within a synapse enables the brain to decide how and when to use them while thinking and processing information.”
Insights from genetically modified mice
Table of Contents
Initially, the research explored endocytosis, the process by which brain cells recycle synaptic vesicles post-transmission. Intersectin was already known to participate in this. However, when scientists engineered mice lacking the intersectin gene, they found endocytosis remained unaffected. This unexpected finding shifted their focus.
Using advanced fluorescence microscopy, the team observed intersectin physically separating active vesicles from dormant ones. This suggested a more direct role in managing vesicle readiness.
Electron microscopy reveals release regulation
Further examination with electron microscopy provided clearer evidence. In nerve cells of mice without intersectin, synaptic vesicles that should have been at the ready site for neurotransmitter release were absent from the cell membrane.This indicated intersectin’s involvement in regulating release,not just recycling.
“This suggested that intersectin regulates release, rather than recycling, of these vesicles at this location of the synapse,” Watanabe explained.
Capturing vesicle dynamics with zap and freeze
To visualize this in real-time,researchers employed zap and freeze microscopy,allowing them to track vesicle movements with millisecond precision and nanometer resolution. In normal mice, vesicles fused with the brain cell membrane within a millisecond of stimulation, with new vesicles quickly filling the vacated spots within 15 milliseconds.
In normal mice, vesicles fused with the brain cell membrane within one millisecond of stimulation.
However, in mice lacking intersectin, or a related protein called endophilin, this crucial replenishment of release sites faltered. This interruption substantially impedes neurotransmission, which relies on rapid vesicle availability.
“When information is processed in the brain,this replenishment process needs to happen in just a few milliseconds,” Watanabe noted.”When you don’t have vesicles staged and ready to go at the release sites or the active zones, then neurotransmission cannot continue.”
Future avenues of research
These findings establish intersectin as a key player in neurotransmission, deepening our understanding of brain function and offering potential therapeutic targets for conditions like Alzheimer’s disease, Huntington’s disease, and Down syndrome. The research team plans to further investigate how intersectin directs new synaptic vesicles to their crucial release sites.
