Limiting energy in neurons exacerbates epilepsy
Date:
March 24, 2022
Source:
Universite' de Gene`ve
Summary:
Epilepsy, one of the most common neurological disorders, is
characterized by the spontaneous repetition of seizures caused
by the hyperactivity of a group of neurons in the brain. Could
we therefore reduce neuronal hyperactivity, and treat epilepsy,
by reducing the amount of energy supplied to neurons and necessary
for their proper functioning? Researchers discovered that, in mice,
the seizures were actually exacerbated.
FULL STORY ========================================================================== Epilepsy, one of the most common neurological disorders, is characterized
by the spontaneous repetition of seizures caused by the hyperactivity
of a group of neurons in the brain. Could we therefore reduce neuronal hyperactivity, and treat epilepsy, by reducing the amount of energy
supplied to neurons and necessary for their proper functioning? This
was tested by a team led by scientists from the University of Geneva
(UNIGE) and the EPFL. The researchers discovered that, in mice, the
seizures were actually exacerbated. They observed that a reduction in the amount of energy led to an increase in the level of calcium in neurons,
making them hyperexcitable. These dysfunctions could be corrected when
mice were fed a ketogenic diet, which is rich in lipids and has been
used since antiquity. This work is published in the journal eLife.
==========================================================================
Our brain, which represents only 2% of our body weight, consumes more than
20% of the sugar we ingest. This considerable need for sugar provides the energy necessary for the function of the billions of neurons responsible
for the emission and propagation of nervous messages, via electrical
signals. This conversion of sugar, and more precisely of glucose, into
energy is carried out by the mitochondria, small intracellular organelles considered as the "energy factories" of the cell.
The key role of the cell's "energy factories" The laboratory of
Jean-Claude Martinou, professor in the Department of Molecular
and Cellular Biology at the Faculty of Science, is interested in
how mitochondria work. His group had already discovered the universal
carrier that allows pyruvate, a product of glucose catabolism, to enter
into mitochondria.
He is now investigating the role of the mitochondrial pyruvate carrier
(MPC) in neuronal activity and whether a defect in the transport of
pyruvate in mitochondria could be linked to certain neurological diseases, notably epilepsy.
Epileptic seizures are the manifestation of cerebral hyperactivity
resulting from hyperexcitation of neurons, often in the cerebral
cortex. "It seemed interesting to us to test whether suppression
of the mitochondrial pyruvate carrier, and thus the decrease in the
amount of energy supplied by the mitochondria, could reduce neuronal hyperexcitability occurring during epileptic seizures," explains
Jean-Claude Martinou, last author of the study.
Mice lacking the MPC are prone to epileptic seizures The biologists administered a pro-epileptic drug, capable of inducing epileptic
seizures, to normal mice and to mice whose cortical neurons lacked the
MPC. In normal mice, injection of a low dose of the drug did not induce seizures. On the other hand, and contrary to the initial hypothesis,
in mice lacking the MPC, very severe, even fatal, seizures occurred as
soon as low doses of the pro-epileptic drug were administered.
Upon further analysis of what was happening in these neurons, the
biologists found that the neurons without MPC had abnormally high
levels of calcium, a crucial element for the proper transmission of
nerve messages. "Pyruvate imported into mitochondria not only plays
the role of a fuel for the cell, but it also allows mitochondria to
sequester calcium. It turns out that it is this second function that is involved in the triggering of epileptic seizures. Since it is no longer
trapped by the mitochondria, the calcium remains free in neurons and
its concentration increases, which makes the neurons hyperexcitable,"
explains Carmen Sandi, professor at EPFL and coauthor of the study.
The secrets of the ketogenic diet Since ancient times, patients suffering
from epilepsy have found that a ketogenic diet, rich in fats and low in carbohydrates, allows them to avoid seizures. Ketone bodies, produced
during a ketogenic diet or fasting, are produced by the breakdown of
lipids in the liver. They are imported into the brain for which they
represent an essential energy source, especially during a fast. They
can enter mitochondria without the need of carriers and are used to
provide energy.
"We found that MPC-deficient mice fed on a ketogenic diet or treated
with ketone bodies had much less severe seizures. With this diet, the
functions of mitochondria and neurons are restored, and the calcium level
is normal," said Marine Laporte, researcher in the Department of Molecular
and Cellular Biology and co-first author of the study. This work, financed
by the Swiss National Science Foundation and the Kristian Gerhard Jebsen Foundation, helps to explain the epileptic seizures frequently observed
in patients with mitochondrial pathologies as well as to consider a
treatment based on ketone bodies, less drastic than ketogenic diets.
========================================================================== Story Source: Materials provided by Universite'_de_Gene`ve. Note:
Content may be edited for style and length.
========================================================================== Journal Reference:
1. Andres De La Rossa, Marine H Laporte, Simone Astori, Thomas
Marissal,
Sylvie Montessuit, Preethi Sheshadri, Eva Ramos-Ferna'ndez, Pablo
Mendez, Abbas Khani, Charles Quairiaux, Eric B Taylor, Jared Rutter,
Jose' Manuel Nunes, Alan Carleton, Michael R Duchen, Carmen Sandi,
Jean-Claude Martinou. Paradoxical neuronal hyperexcitability in
a mouse model of mitochondrial pyruvate import deficiency. eLife,
2022 DOI: 10.7554/ eLife.72595 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/03/220324104443.htm
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