The surprising metabolism of “exercising” neurons, by Jaime de Juan Sanz

The brain is an expensive organ: while it only represents 2.5% of total body mass it accounts for 20% of the energy expenditure in our body. In particular, neurons consume high amounts of energy when they communicate to one another during the process known as synaptic transmission, in which a neuron releases neurotransmitters that will be received and “understood” by the next neuron. Synaptic transmission is continuously taking place and therefore the brain is never in a fully “resting” state; on the contrary, it undergoes rapid and intense changes in activity, requiring increased amounts of energy in more active regions to maintain function. To get an idea on how intense can be the activation of certain regions in the brain during cognitive function, a spectacular example can be observed in the recordings of neuronal activity in zebrafish brains by the Ahrens’ lab at Janelia Research Campus: visualizing at least 80% of the neurons of the brain in action we can see the “electrical storm” of swimming zebrafish “thinking”!

Video 1. Visualization of neuronal activity in the zebrafish brain using GCaMP indicators. | Credit: Ahrens Lab, HHMI/Janelia Research Campus.

Not surprisingly, failures in supplying energy to the brain rapidly result in cognitive dysfunction, for example during bouts of hyperglycemia or ischemic events, leading to profound and immediate suppression of neuronal function. Neurons seem to be particularly dependent on energy availability and therefore scientists have long thought that they maintained a large and steady amount of energy available to be used at any moment. However, research in the recent years by the labs of Timothy Ryan at Weill Cornell Medicine and Daniel Colon-Ramos at Yale University have discovered that energy in neurons is produced on an as-needed basis during neuronal activity at the presynaptic terminal, where neurotransmission is initiated. Neurons utilize glucose during activity to produce ATP, the intracellular fuel used by any cell, and use that newly-generated ATP to restore neuronal processes to be able to transmit information again in the next cycle (1, 2). How this is possible at the biochemical level, however, was not well understood until now.

Ashrafi et al. report in the Jan. 19th issue of Neuron (3) that neurons produce energy on demand using the same mechanism as muscle cells during exercise. The team found that synapses can increase the production of ATP from glucose during activity by sequestering additional glucose from the media surrounding the neuron: active neurons mobilize more copies of a glucose transporter, GLUT4, to the neuronal surface, which allows increasing the ability of the neuron to capture glucose to use it to generate energy in the form of ATP. For neuroscientist this is unprecedented since despite the uncountable differences between contracting muscle cells and neurons, the mechanism that allows both of them to “exercise” is basically the same. The researchers also explored some of the details on how this is possible and discovered that many features at the molecular level are conserved when compared to muscle cells, meaning that “exercising” synapses are a lot like exercising muscle. Ashrafi et al. discovered that when neurons begin to release neurotransmitters, the enzyme AMPK (AMP-activated kinase) is activated. This enzyme acts as a metabolic sensor in many cells to monitor subtle changes in energy availability and whenever energy is starting to be spent to transmit information, AMPK is activated and induces the insertion of more copies of GLUT4 on the cell surface. The researchers also demonstrate that if they experimentally block either AMPK activation or GLUT4’s ability to capture glucose, neurons are unable to sustain synaptic transmission for more than a few seconds. This is of tremendous importance for the brain since cognitive function relies on accurate and continuous neuronal function and demonstrates how essential neuronal metabolism is for synaptic transmission.

Since insulin has been shown to mobilize GLUT4 to the surface in muscle and fat cells, this research opens a new important question: is it possible that insulin may affect/tune brain function? Surely we will see more research on this in the future!

References 

1. Rangaraju, V., Calloway, N., & Ryan, T. A. (2014). Activity-driven local ATP synthesis is required for synaptic function. Cell, 156(4), 825-835.
2. Jang, S., Nelson, J. C., Bend, E. G., Rodríguez-Laureano, L., Tueros, F. G., Cartagenova, L., … & Colón-Ramos, D. A. (2016). Glycolytic enzymes localize to synapses under energy stress to support synaptic function. Neuron, 90(2), 278-291.
3. Ashrafi, G., Wu, Z., Farrell, R. J., & Ryan, T. A. (2017). GLUT4 Mobilization Supports Energetic Demands of Active Synapses. Neuron. 93,1-10

Any views expressed are those of the author, and do not necessarily reflect those of PLOS. 

Jaime de Juan-Sanz holds an M.Sc. in Molecular Biomedicine from Universidad Autónoma de Madrid and a Ph.D. in Molecular Neurobiology obtained at Centro de Biología Molecular “Severo Ochoa” (CBMSO). He is currently a postdoctoral associate at Weill Cornell Medical College (Cornell University) in New York City where he is investigating the molecular basis of synaptic transmission, studying biophysical aspects of synaptic biology. He is also interested in encouraging open science in our society promoting open access research and science outreach. You can follow him on twitter @JaimedeJuan