Energy Is Essential To Build (and Destroy) Neural Connections

The bodies of animals and humans are innervated by a network of nerve cells which are connected through long extensions. The nerve cells use these so-called axons and dendrites to communicate with one another. During early development, nerve cells grow a large number of axons and dendrites. To make the connections specific, redundant extensions are removed at a later stage in a process called “pruning”. Using the fruit fly Drosophila melanogaster as a model, an interdisciplinary team of researchers at the University of Münster (Germany) asked whether energy (in the form of adenosine triphosphate (ATP)) is needed for pruning, which takes place in the flies during metamorphosis. The results of the study have now been published in the journal “Cell Reports”.

Some background: ATP is the energy currency of all living cells. Because it is so important, there are many different ways of producing it – for example, through the process of glycolysis from glucose or by so-called oxidative phosphorylation from various other nutrients. “The reason that we asked whether ATP is important for pruning comes from observations of the fruit fly,” explains Marco Marzano, a member of the team led by Dr. Sebastian Rumpf at the Institute of Neuro- and Behavioural Biology and lead author of the study. “Firstly, in Drosophila most pruning happens during the pupal stage when the animals do not feed and have to be very careful with their stored resources. And secondly, a fundamental question: Is energy needed when a biological structure breaks down?”

Marzano observed that nerve cells did not properly prune their dendrites when they lacked an important regulator of energy metabolism. This factor – the so-called AMP-activated protein kinase (AMPK) – normally safeguards cells from consuming too much energy. With the help of members of Prof. Erez Raz’s research group at the Centre for Molecular Biology of Inflammation, Marzano set up a sensor system which enabled him to measure the ATP content in the nerve cells. In this way he was able to show that AMPK specifically promotes ATP generation through oxidative phosphorylation. Another collaboration with the “Medical Cell Biology” team led by Prof. Michael Krahn (Faculty of Medicine and Münster University Hospital) made it possible to measure the activity of AMPK directly, revealing that AMPK is activated by an important development regulator. “This indicates that a constant supply of energy seems to be especially important for pruning,” says Sebastian Rumpf. “One reason for this may be that some of the pruning enzymes need to be produced just before the process.”

Interestingly, the team was able to demonstrate that the defects in nerve development were intensified by malnutrition. The results thus show important connections between nerve development, cellular energy metabolism and the general energy supply. It was already known from studies on neurodegenerative diseases that nerve cells can atrophy when their energy balance is disturbed. This new study shows that sufficient, precisely regulated energy supply is already decisive for nerve development at an early stage – and not only for the growth of nerve processes, but also for their degradation.

For their studies, the researchers combined modern microscopy techniques – such as sensors based on Förster resonance energy transfer (FRET), – with molecular Drosophila genetics.

Reference: Marzano M, Herzmann S, Elsbroek L, et al. AMPK adapts metabolism to developmental energy requirement during dendrite pruning in Drosophila. Cell Rep. 2021;37(7). doi: 10.1016/j.celrep.2021.110024

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