Pound for pound, the brain consumes vastly more energy than other organs, and, puzzlingly, it remains a fuel-guzzler even when its neurons are not firing signals called neurotransmitters to each other. Now researchers at Weill Cornell Medicine have found that the process of packaging neurotransmitters may be responsible for this energy drain.

In their study, reported Dec. 3 in Science Advances, they identified tiny capsules called synaptic vesicles as a major source of energy consumption in inactive neurons. Neurons use these vesicles as containers for their neurotransmitter molecules, which they fire from communications ports called synaptic terminals to signal to other neurons. Packing neurotransmitters into vesicles is a process that consumes chemical energy, and the researchers found that this process, energy-wise, is inherently leaky—so leaky that it continues to consume significant energy even when the vesicles are filled and synaptic terminals are inactive.

These findings help us understand better why the human brain is so vulnerable to the interruption or weakening of its fuel supply.
Senior author Dr. Timothy Ryan, a professor of biochemistry and of biochemistry in anesthesiology at Weill Cornell Medicine.

Dr. Ryan and his laboratory have shown in recent years that neurons’ synaptic terminals, bud-like growths from which they fire neurotransmitters, are major consumers of energy when active, and are very sensitive to any disruption of their fuel supply. In the new study they examined fuel use in synaptic terminals when inactive, and found that it is still high.

This high resting fuel consumption, they discovered, is accounted for largely by the pool of vesicles at synaptic terminals. 

The researchers discovered that there is essentially a leakage of energy from the vesicle membrane, a “proton efflux,” such that a special “proton pump” enzyme in the vesicle has to keep working, and consuming fuel as it does so, even when the vesicle is already full of neurotransmitter molecules.

The experiments pointed to proteins called transporters as the likely sources of this proton leakage. 

Although the leakage per vesicle would be tiny, there are at least hundreds of trillions of synaptic vesicles in the human brain, so the energy drain would really add up, Dr. Ryan said.

The finding is a significant advance in understanding the basic biology of the brain. In addition, the vulnerability of the brain to the disruption of its fuel supply is a major problem in neurology, and metabolic deficiencies have been noted in a host of common brain diseases including Alzheimer’s and Parkinson’s disease. This line of investigation ultimately could help solve important medical puzzles and suggest new treatments.

If we had a way to safely lower this energy drain and thus slow brain metabolism, it could be very impactful clinically.
Dr. Ryan


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