Limiting energy in neurons exacerbates epilepsy —


Epilepsy, some of the widespread neurological issues, is characterised by the spontaneous repetition of seizures attributable to the hyperactivity of a gaggle of neurons within the mind. Might we due to this fact cut back neuronal hyperactivity, and deal with epilepsy, by lowering the quantity of power equipped to neurons and mandatory for his or her correct functioning? This was examined by a workforce led by scientists from the College of Geneva (UNIGE) and the EPFL. The researchers found that, in mice, the seizures have been really exacerbated. They noticed {that a} discount within the quantity of power led to a rise within the degree of calcium in neurons, making them hyperexcitable. These dysfunctions might be corrected when mice have been fed a ketogenic food plan, which is wealthy in lipids and has been used since antiquity. This work is printed within the journal eLife.

Our mind, which represents solely 2% of our physique weight, consumes greater than 20% of the sugar we ingest. This appreciable want for sugar supplies the power mandatory for the perform of the billions of neurons accountable for the emission and propagation of nervous messages, by way of electrical indicators. This conversion of sugar, and extra exactly of glucose, into power is carried out by the mitochondria, small intracellular organelles thought-about because the “power factories” of the cell.

The important thing position of the cell’s “power factories”

The laboratory of Jean-Claude Martinou, professor within the Division of Molecular and Mobile Biology on the School of Science, is excited about how mitochondria work. His group had already found the common service that permits pyruvate, a product of glucose catabolism, to enter into mitochondria. He’s now investigating the position of the mitochondrial pyruvate service (MPC) in neuronal exercise and whether or not a defect within the transport of pyruvate in mitochondria might be linked to sure neurological illnesses, notably epilepsy.

Epileptic seizures are the manifestation of cerebral hyperactivity ensuing from hyperexcitation of neurons, usually within the cerebral cortex. “It appeared fascinating to us to check whether or not suppression of the mitochondrial pyruvate service, and thus the lower within the quantity of power equipped by the mitochondria, might cut back neuronal hyperexcitability occurring throughout epileptic seizures,” explains Jean-Claude Martinou, final creator of the research.

Mice missing the MPC are liable to epileptic seizures

The biologists administered a pro-epileptic drug, able to inducing epileptic seizures, to regular mice and to mice whose cortical neurons lacked the MPC. In regular mice, injection of a low dose of the drug didn’t induce seizures. However, and opposite to the preliminary speculation, in mice missing the MPC, very extreme, even deadly, seizures occurred as quickly as low doses of the pro-epileptic drug have been administered.

Upon additional evaluation of what was taking place in these neurons, the biologists discovered that the neurons with out MPC had abnormally excessive ranges of calcium, an important factor for the correct transmission of nerve messages. “Pyruvate imported into mitochondria not solely performs the position of a gas for the cell, however it additionally permits mitochondria to sequester calcium. It seems that it’s this second perform that’s concerned within the triggering of epileptic seizures. Since it’s not trapped by the mitochondria, the calcium stays free in neurons and its focus will increase, which makes the neurons hyperexcitable,” explains Carmen Sandi, professor at EPFL and coauthor of the research.

The secrets and techniques of the ketogenic food plan

Since historical occasions, sufferers affected by epilepsy have discovered {that a} ketogenic food plan, wealthy in fat and low in carbohydrates, permits them to keep away from seizures. Ketone our bodies, produced throughout a ketogenic food plan or fasting, are produced by the breakdown of lipids within the liver. They’re imported into the mind for which they symbolize a necessary power supply, particularly throughout a quick. They’ll enter mitochondria with out the necessity of carriers and are used to supply power.

“We discovered that MPC-deficient mice consumed a ketogenic food plan or handled with ketone our bodies had a lot much less extreme seizures. With this food plan, the capabilities of mitochondria and neurons are restored, and the calcium degree is regular,” stated Marine Laporte, researcher within the Division of Molecular and Mobile Biology and co-first creator of the research. This work, financed by the Swiss Nationwide Science Basis and the Kristian Gerhard Jebsen Basis, helps to elucidate the epileptic seizures often noticed in sufferers with mitochondrial pathologies in addition to to contemplate a therapy based mostly on ketone our bodies, much less drastic than ketogenic diets.