In terms of energy consumption, the brain consumes more than any other organ, even when its neurons are not exchanging messages known as neurotransmitters with one other. Now, researchers at Weill Cornell Medicine have discovered that the packing of neurotransmitters may be the reason for this drain on energy.
Synaptic vesicles, a small capsule, have been discovered as a critical source of energy consumption in dormant neurons in research published in Science Advances today.
Neurons store their neurotransmitter molecules in these vesicles, which they fire from synaptic terminals, the communication ports they use to communicate with other neurons. Chemical energy is required to pack neurotransmitters into the vesicles, which is why the study team discovered that the process itself was leaky, using energy even if the vesicles were full and synaptic terminals were dormant. Senior author Dr. Timothy Ryan, a professor of biochemistry and anesthesiology biochemistry at Weill Cornell Medicine, stated, "These discoveries help us understand better why the human brain is so sensitive to the stoppage or weakening of its fuel supply.
Studies of the brain's fuel usage in comatose (relating to or in a state of coma) and vegetative states have found that the brain uses a lot of energy even when it is at rest. Although the brain's glucose consumption declines by around half in these deeply inactive states, it remains a significant energy consumption compared to other organs. Those resting energy drains have never been completely understood.
Neurons' synaptic terminals, the bud-like growths from which they fire neurotransmitters, are substantial energy consumers while active and are very sensitive to any disturbance in their fuel supply, according to new research by Dr. Ryan and his colleagues. In a recent study, researchers looked at synaptic terminal fuel usage when the neurons were dormant and discovered it was still high. Scientists found that the vesicle pool at synaptic terminals accounts for a significant portion of this high resting fuel consumption. Inactive synapses allow vesicles to be filled with thousands of neurotransmitters apiece and ready to be launched across synapses to their partner neurons.
It's unclear why a synaptic vesicle would use energy even when it's complete. The researchers observed a "proton efflux," or energy leakage from the vesicle membrane, which forces a particular "proton pump" enzyme in the vesicle to keep functioning, spending fuel in the process, even when the vesicle is already packed with neurotransmitter molecules.
According to the results of the tests, proton leakage may be caused by proteins known as transporters. A proton may escape when transporters change shape to deliver neurotransmitters into vesicles; however, this is not the case in all cases. It is possible that this transporter shape-shift was set low by evolution to facilitate quicker reloading of neurotransmitters during synaptic activity, and hence faster thought and action.
"The transporter's shape-shifting may be triggered by random thermal fluctuations, generating this constant energy loss even when no neurotransmitter is being loaded," he added.
However, Dr. Ryan added that even a modest amount of energy would be lost in each synaptic vesicle since there are at least hundreds of trillion of these vesicles in our brains. The discovery is a significant step forward in our knowledge of the brain's fundamental biochemistry. Alzheimer's disease and Parkinson's disease are only two examples of frequent brain disorders linked to a deficiency in the brain's capacity to get fuel. Ultimately, this research might lead to the discovery of vital medical mysteries and the development of novel medicines.
Camila Pulido, Timothy A. Ryan, “Synaptic vesicle pools are a major hidden resting metabolic burden of nerve terminals”, 3 December 2021, Science Advances, Vol 7, Issue 49. DOI: 10.1126/sciadv.abi9027