The brain uses far more energy than any other organ, and inexplicably, even when neurons aren’t emitting signals called neurotransmitters to each other, the brain uses a lot of fuel. Now, Weill Cornell Medicine researchers have discovered that the process of packaging neurotransmitters may be responsible for this energy drain.
Their study, reported Dec. 3 in Science Advances, identified tiny capsules called synaptic vesicles as the main source of energy expenditure in inactive neurons. Neurons use these vesicles as containers for neurotransmitter molecules, which fire from communication ports called synaptic terminals to send signals to other neurons. Packing neurotransmitters into vesicles is a process that consumes chemical energy, and the researchers found that this process is inherently leaky from an energy standpoint. Because they are so leaky, they continue to expend large amounts of energy even when the vesicles are full and the synaptic terminals are inactive.
“These findings help us better understand why the human brain is so vulnerable to interruptions or weakening of its fuel supply,” said Professor of Biochemistry and Anesthesiology, Department of Biochemistry, Weill Cornell Medical College. said senior author Dr. Timothy Ryan, a professor at .
The observation that the brain uses large amounts of energy even when at relative rest dates back several decades to studies of the brain’s fuel consumption during coma and vegetative states. These studies show that even in this state of extreme inactivity, the brain’s glucose consumption is typically reduced by only about half of normal, and the brain remains a high energy consumer compared to other organs. It has been found. The causes of energy drain during resting are not completely understood.
Dr. Timothy Ryan.Credit: Travis Curry
Dr. Ryan and his lab have shown that neurons’ synaptic terminals (bud-like growths that release neurotransmitters) are major consumers of energy when active and are highly sensitive to interruptions in fuel supply. Shown in recent years. The new study looked at fuel usage at synaptic terminals. inI found it to be active but still high.
They found that the main cause of this high resting fuel consumption is a pool of vesicles at synaptic terminals. When a synapse is inactive, each vesicle is loaded with thousands of neurotransmitters and is ready to send its signal-carrying payload across the synapse to its partner neuron.
Why do synaptic vesicles expend energy even when fully loaded? The researchers found that there is essentially a leakage of energy from the vesicle membrane, or “proton efflux,” so that synaptic vesicles expend energy even when fully loaded. They discovered that special “proton pump” enzymes inside the cells have to keep working, consuming fuel to do so. The vesicles are already filled with neurotransmitter molecules.
The experiments pointed out that proteins called transporters may be responsible for this proton leakage. Transporters normally bring neurotransmitters into vesicles and change their shape to transport the neurotransmitters, but they also allow protons to escape. Ryan speculates that evolution may have set a lower energy threshold for this transporter to change shape, allowing it to reload neurotransmitters more quickly during synaptic activity, thereby speeding up thought and action. .
“The downside to faster loading capabilities is that even random thermal fluctuations can cause shape changes in the transporter, causing this continued energy depletion even when no neurotransmitter is loaded.” he stated.
Although the leakage amount per vesicle is tiny, Ryan says, the human brain has at least hundreds of trillions of synaptic vesicles, so the energy drain would actually be huge.
This discovery represents a major advance in understanding the basic biology of the brain. Furthermore, the brain’s vulnerability to interruptions in fuel supply is a major problem in neurology, and metabolic dysfunction has been implicated in many common brain diseases, including Alzheimer’s and Parkinson’s diseases. This line of research could ultimately help solve important medical mysteries and suggest new treatments.
“If we had a way to safely lower this energy expenditure and reduce brain metabolism, this could have a huge clinical impact,” Dr. Ryan said.
