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Granule cells – how do neurons “speak”?

Emergency situations tend to reveal the true character of a person, and the same thing happens with cells. Temporal lobe epilepsy puts human brain cells into an emergency situation. Dr. Jakob Wolfart, junior professor at the Neurocentre at the Freiburg University Medical Centre and his team are investigating how the behaviour of neurons changes upon the onset of electrical chaos in the hippocampus. Changes in the flow of electrical charge at the cell membranes provide information about disease mechanisms as well as details about the “normal” functions of neurons, and hence the syntax of the electrochemical “language” which neurons use to communicate with each other.

Neurons in the human brain produce electrical signals and transfer them to other neurons. This “language” is based on ion channels located in the cell membranes. The transfer of ions across the membrane leads to voltage changes. In theory, the large number of possible ion channel type combinations in the human brain would be able to generate an unlimited number of electrical activity patterns, representing an unlimited possibility to form words and create sentences. However, every type of neuron has its defined word pool and a defined number of grammar rules. “Why does each nerve cell type speak its own particular language?” asks Dr. Jakob Wolfart, head of the “Cellular Neurophysiology” group at the Neurocentre at the Freiburg University Medical Centre. “This is based on a specific repertoire of ion channels in the cell membrane and the electrophysiological behaviour of these ion channels.”

Who will survive?

Junior professor Dr. Jakob Wolfart sitting in front of the experimental set-up which he uses to measure the time course of the voltage in neurons. © Dr. Jakob Wolfart

Wolfart is a biologist by training. He hopes that some time in the future he will be able to understand the basis of the Babylonian language diversity in the human brain. He has been focussing on individual neural cell types for many years and investigating the composition of their ion channels and their electrophysiological characteristics. As an independent work group leader in the Epilepsy Centre at the Freiburg University Medical Centre, he has the rare opportunity to investigate the living brain tissue of epilepsy patients. Severe temporal lobe epilepsy might lead to irreversible hippocampal damage which requires the hippocampus to be removed. Large numbers of the cells that make up its major mass die during the uncontrolled discharge of electrophysiological activity that is typical of epileptic seizures. The only cells that remain relatively intact during temporal lobe epilepsy are the granule cells of the brain region known as “dentate gyrus” that acts as a type of gate into the hippocampus. “This is why many scientists believe that these granule cells are associated with temporal lobe epilepsy,” said Wolfart who does not personally believe that the granule cells trigger the chaos associated with epileptic seizures. He is nevertheless interested in the changes in their activity. This is because the comparison of normal and defective behaviour enables conclusions to be drawn on the mechanisms of electrochemical activity that leads to the characteristic behaviour of a granule cell, both in normal and diseased situations.

The figure shows the reconstruction of a patient’s granule cell (green). The patient’s hippocampus had to be surgically removed for seizure control. The cell nuclei of surrounding granule cells are shown in red (labelled with mitProx1). 100 µm scale bar. © Dr. Jakob Wolfart

Wolfram and his team cut the brain tissue into thin slices immediately after it has been surgically removed from patients’ brains. “This provides us with granule cells that are in a relatively natural state. This also enables us to investigate individual cells,” said Wolfart. The researchers use patch clamp electrodes to record the voltage at the cell membranes. They also use toxins that selectively block certain ion channels to manipulate the voltage. This provides them with information as to which ion channels are active in granule cells that have been removed from epilepsy patients and responsible for the electrical behaviour of the cells. “It is known that epileptic seizures are caused by uncontrolled rapid sequences of electrical discharges. In addition, it has been suggested that granule cells that survive temporal lobe epilepsy are hyperexcitable and play an important role in the generation of epileptic seizures,” said Wolfart. “However, we found exactly the opposite: the granule cells seem to be fully sedated and can only be excited with great difficulty.”

The molecular basis of neuronal dialects

Wolfart and his team found their results difficult to believe and decided to carry out many other experiments including control experiments in mice. They eventually found that the “drowsiness” of the granule cells was due to the activity of certain potassium channels. Potassium channels normally attenuate the excitability of nerve cells. Using toxins and antibody tests, Wolfart and his team were able to show that several types of potassium channel contributed to the altered behaviour of the granule cells. “What role do these potassium channels play in healthy granule cells?” asks Wolfart. “If a cell upregulates a certain group of ion channels in disease situations, it can be assumed that this particular type of channel has already previously played a role and could be an important “switch”. The researchers from Freiburg will carry out further measurements and set up computer models to find out how the network of ion channels leads to the typical behaviour of granule cells.

In another project, the electrophysiologist Wolfart intends to compare the particular channel make-up with that of other cell types. “Why do granule cells have this particular combination of ion channels in their membrane?” asks Wolfart. “What makes them the cells of choice at the entry region to the hippocampus? How does their channel make-up correspond with their function in the brain network?” The diversity of different “languages” in our brain is the basis of human thinking, feeling and remembering. Using granule cells as study objects, Wolfart can make a small step towards the detailed understanding of these phenomena.

Further information:

Junior professor Dr. Jakob Wolfart
Cellular Neurophysiology
Neurocentre
Freiburg University Medical Centre
Breisacherstr. 64
79106 Freiburg
Tel.: +49-(0)761-270-52850
E-mail: jakob.wolfart(at)uniklinik-freiburg.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/granule-cells-how-do-neurons-speak