Abstract
The human brain has about 109 wires (neurons) and about 1012 connections (synapses). The speed of information processing is therefore limited by the speed of synapses, in particular the time it takes for the neurotransmitter molecules to be released. Transmitters are stored at nerve endings in tiny packets called synaptic vesicles that fuse with the nearby cell membrane when required. This process of membrane fusion is the most evolved in nature, taking only ~100 µsec in humans and even in simple invertebrates. Though it employs the same core protein machinery (SNARE proteins), synaptic vesicle fusion is 103 - 104 times faster than any other fusion process in the body.
About 10 years ago we set out to understand how this is possible. We succeeded in reconstituting this “turbocharged” process from pure proteins and lipids in synthetic synaptic vesicles and cell membranes representing all of the required genes. In essence, we have found that the synapse has evolved a remarkable strategy for investing the energy made available when naturally unfolded alpha helices assemble into pin-like stable coiled-coils between the two membranes. Six such “Central” SNARE complexes form an inner ring responsible for fusion per se. When alone, they release content progressively over ~1 sec. When surrounded by a second ring of six “Peripheral” SNARE complexes release is now turbocharged, occurring all at once in <1 msec. The outer ring pulls on the membrane surrounding the synaptic vesicle, raising the hydrostatic pressure inside to ~3 atmospheres, an elegant example of evolution reaching to the limits of physics. Intracellular signaling G Proteins, physiologically controlled by neuro-modulatory transmitters like Serotonin and Dopamine, toggle the vesicle from 12 to 6 SNAREs, thereby switching the pattern of release.
We predict this changes the manner in which the synapse is used, most likely from rapid information processing to memory storage. Synaptic genes causing certain cognitive and movement disorders prevent the outer ring from assembling and this locks the vesicles into the slow-release mode. It is likely that there are yet other modes of transmission that rely on physical principles remaining to be discovered.
