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 diseases. But pound for pound, the brain consumes far more energy than other organs. Researchers at Weill Cornell Medicine have now found that the process of packaging neurotransmitters into vesicles may be responsible for this energy drain. Their studies, reported in Science Advances, provide important new insights that could help scientists better understand basic brain biology. This line of investigation could ultimately help to answer important medical queries and point to new treatments, the researchers suggested.

“These findings help us understand better why the human brain is so vulnerable to the interruption or weakening of its fuel supply,” said Timothy Ryan, PhD, a professor of biochemistry and of biochemistry in anesthesiology at Weill Cornell Medicine. Senior author Ryan, together with co-author Camila Pulido, PhD, reported on their studies in a paper titled, “Synaptic vesicle pools are a major hidden resting metabolic burden of nerve terminals,” in which they concluded, “Our findings underscore why nerve terminals are susceptible to metabolic compromises, as in addition to regulating ATP production in responses to activity, they must constantly meet a large local metabolic burden.”

The brain is a “metabolically fragile “ organ, the authors wrote, and interruption to its supply of glucose fuel and oxygen can rapidly degrade cognitive function, and lead to “severe neurological impairment.” As the team continued, “The human brain generally has a very small safety factor with respect to fuel supply, such that when blood glucose levels drop by only ~2-fold, severe neurological consequences ensue.” But the brain is also very energetically expensive, they noted, and is estimated to consume ~8–10 times the amount of energy per weight compared to average tissue. In fact, while the brain consumes ~20% of the body’s fuel intake, it represents only ~2–2.5% of the mass, the scientists noted.

Puzzlingly, the brain remains a fuel-guzzler even when its neurons are not firing neurotransmitter signals to each other. The observation that the brain consumes a high amount of energy, even when relatively at rest, dates back several decades to studies of the brain’s fuel use in comatose and vegetative states. Those studies found that even in these profoundly inactive states, the brain’s consumption of glucose typically drops from normal by only about half—which still leaves the brain as a high consumer of energy relative to other organs. The sources of that resting energy drain have never been fully understood.

The Ryan lab has shown in recent years that synaptic terminals—the bud-like growths on neurons from which neurotransmitters are fired—are major consumers of energy when active, and are very sensitive to any disruption of their fuel supply. In their newly reported study, Ryan and Pulido examined fuel use in inactive synaptic terminals, and found that it is still high. “To determine whether nerve terminal metabolic vulnerability might be driven by local basal metabolic rates, we designed experiments to characterize this parameter and to uncover its molecular underpinning,” they wrote.

They identified the synaptic vesicles (SVs) as a major source of energy consumption in inactive neurons. Neurons use these vesicles as containers for the neurotransmitter molecules, which they fire from 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.

This high level of resting-state fuel consumption, they discovered, is accounted for largely by the pool of vesicles at synaptic terminals. During synaptic inactivity, vesicles are fully loaded with thousands of neurotransmitters each, and are ready to launch these signal-carrying payloads across synapses to partner neurons.

So why would a synaptic vesicle consume energy even when fully loaded? 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. “… we show that nerve terminals have a high resting metabolic energy demand, independent of electrical activity, and that SV pools are a major source of basal energy consumption in this compartment …,” they wrote. “We demonstrate that this basal metabolism arises from SV-resident vacuolar-type ATPase (V-ATPases) compensating for a previously unknown constant H+ efflux from the SV lumen.”

The experiments pointed to proteins called transporters as the likely sources of this proton leakage. Transporters normally bring neurotransmitters into vesicles, changing shape to carry the neurotransmitter in, but allowing at the same time for a proton to escape, as they do so. “We show that this steady-state H+ efflux (i) is mediated by vesicular neurotransmitter transporters, (ii) is independent of the SV cycle, (iii) accounts for up to 44% of the resting synaptic energy consumption, and (iv) contributes significantly to nerve terminal intolerance of fuel deprivation,” the team stated.

Ryan speculates that the energy threshold for this transporter shape-shift was set low by evolution to enable faster neurotransmitter reloading during synaptic activity, and thus faster thinking and action. “The downside of a faster loading capability would be that even random thermal fluctuations could trigger the transporter shape-shift, causing this continual energy drain even when no neurotransmitter is being loaded,” he said.

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

“Our studies provide a compelling explanation for the reason nerve terminals are so sensitive to metabolic compromise and, in turn, potentially speak to why brain tissue, in general, has a resting metabolic rate that is much higher than other tissues,” the authors concluded. “These data have profound implications with respect to how energy balances across synapses in the brain are achieved and whether different neuronal populations might be more vulnerable than others to presynaptic metabolic compromise due to the total load created by these SV pools.”