Package not delivered: your leaky neurotransmitters and you

BioTechniques News
Aisha Al-Janabi

Even when inactive, the brain guzzles energy in a way that would give supply chain experts heart palpitations, and researchers at Weill Cornell Medicine think that neurotransmitters may explain why.

It has occasionally been noted by engineers that while evolution has created a technical and surprisingly functional achievement in the human body, from a design perspective evolution could stand to take a couple of foundation courses in efficiency and planning. The best-known exemplification of this is the arguably lamentable execution of the human eye, which some now conceive of as a well-intentioned but fundamental misadventure that never quite made it past the prototyping stage before release.  

What about the brain? Surely you can’t criticize the brain? You’d think that, but you’d be wrong. For a start, some consideration for aesthetics might not go to waste. Unless you’re a particular fan of lumpen bread-accidents, it’s not much of a looker. The storage system is a tad arcane, too. When’s your mother’s birthday? You don’t know. How many sugars does Sally take in her coffee? You asked her 10 seconds ago. You don’t know. But you will rhythmically grind your teeth into moist splinters as you recite every single lyric of that song that you hate from 2 decades ago, on a loop, while you try to fall asleep every night. To top it off, at a more fundamental level, the brain is a bit of a biological SUV – impressive, perhaps, but about as cost-effective to run as a Kopi luwak-powered jet engine. In fact, researchers have observed that the brain consumes a significant amount of fuel even when its neurons aren’t sending signals to each other.  

In our modern world of 24-hour deliveries and warehouses, the reason for this exaggerated energy consumption may be more relatable than you’d think, according to researchers at Weill Cornell Medicine (NY, USA). Studies dating back several decades observed that the brain in comatose and vegetative states still consumes glucose at roughly half the normal rate, despite an extreme lack of activity. To send a neurotransmitter between neurons, a neuron must first package that neurotransmitter into a tiny capsule known as a synaptic vesicle. They fire those containers from communications ports called synaptic terminals, thereby passing the signal to other neurons. It turns out that this packaging process constitutes a significant source of chemical energy consumption, even in inactive neurons.  

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While the sources of this excessive energy consumption are yet to be completely understood, the reason for this seems to boil down to bad packaging. The result is that even when the synaptic vesicles are fully loaded, they continue to consume energy. The researchers observed an energy leak from the vesicle membrane known as the proton efflux. The transporter proteins bring neurotransmitters into vesicles, changing shape as they do so. It’s thought that this may be the source of the leak, with protons escaping during this transitional phase. While the leakage of each individual vesicle is effectively negligible, the cumulative leakage of hundreds of trillions of vesicles is substantial. In turn, this means that an enzyme responsible for proton supply continues to supply protons even when the vesicle is full.  

So your brain works a bit like if Amazon delivered your packages in an old ship with a couple of holes in the hull because the ship keeps trying to turn into the Batmobile.  

Senior author of the study at Weill Cornell Medicine, Timothy Ryan, has suggested that the energy threshold for the shape-shifting is low in order to facilitate faster reloading during active periods, resulting in faster thinking and action. However, he also noted the drawbacks to this system: 

“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.” 

These findings represent a respectable step forward in our understanding of fundamental neurobiology. Scientists have long been aware of the role of metabolic deficiencies in common brain diseases such as Alzheimer’s and Parkinson’s, and this new information reveals an important part of the broader medical picture, which may in turn lead to solutions and treatments.  

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


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