A biological mechanism that damages a specific type of memory, but at the same time provides resistance to epilepsy, has been found by researchers from the Sagol Department of Neurobiology at the University of Haifa and European researchers.
Research student Elham Taha from the laboratory of Prof. Kobi Rosenblum, who undertook the research, explains:
“In both healthy and sick brains, the relationship between the activities of the nerve cells that cause the transfer of information and activities delaying the transmission of information is extremely important. We know that damage to this relationship forms the basis of various brain diseases, such as neuro-developmental diseases and epilepsy.
The aim of our study was to isolate molecular components that serve the creation of long-term memories. We were surprised to find that the molecular change we created led to a minor change in this relationship in the hippocampus, but also created resistance to epileptic seizures. Thus the finding creates new possibilities for developing drugs for the treatment of epilepsy.”
RNA Protein Translation
As with many scientific discoveries, the researchers came across their finding by chance.
Taha’s doctorate thesis focuses on the study of the underlying processes behind the creation and preservation of memories. More specifically, she is examining the control of RNA to protein translation.
In the present study, the researchers examined what happens to a mouse who has undergone genetic modification causing the total non-expression of the protein eEF2K. Previous studies have shown that damage to this protein causes damage to memory.
The mice underwent a long series of behavioral tests. None of the tests identified damage to the consolidation of memory, with the exception of one specific type of memory: context memory – the memory created relating to the context (usually the spatial context) of learning.
These experiments found specific damage to the function of an area known as the hippocampus.
GABAAR And Synapsin2b
The researchers then wanted to examine the electro-physiological and molecular biology activity in the brains of these mice. They found that the hippocampus shows increased expression of a sub-unit of a receptor called GABAAR.
This receptor is located in the membrane of the nerve cell, and its hyperactivity causes cells to be less active, thereby delaying information rather than transmitting it.
In addition, elevated expression of the protein synapsin2b was also found. This protein is key modulator of neurotransmitter release in neurons.
“We realized that, surprisingly, the change in the general translation control element, eEF2K, changes the excitation/inhibition ratio in a specific area of the brain,” Taha explains. “This area, the Dentate Gyrus in the hippocampus, as well as the molecules whose expression changed, are associated with epilepsy. For example, mutation in synapsin2b in humans or a decline in its expression may lead to epilepsy.”
Epileptic Seizures Gone
So the joint research team then examined whether down regulation of eEF2K that heightens the expression of synapsin2b will influence epilepsy model mice with low expression for this protein. In the first test, the researchers took a male mouse with no expression of eEF2K and a female epilepsy model mouse and bred them.
When epilepsy model mice breed, the offspring are almost always born with epilepsy. In this case, the offspring were born without epileptic seizures, as shown by EEG tests.
In the second test, a substance inhibiting the expression of eEFK2 was injected into mice with epilepsy. EEG tests showed that they did not suffer from epileptic seizures for one week from the time of injection. In both cases, biological examinations showed that the expression of synapsin2b had become normal.
“We effectively managed to cause a situation whereby mice that should have been born with epilepsy were born healthy, and mice that have epilepsy were cured, at least for the duration of time in which the expression of eEF2K was suppressed. The results create a possibility for a better understanding of the excitation/inhibition balance in the hippocampus, a vital area of the brain for cognitive processes that is associated with various cerebral pathologies.
In the next stage, we will attempt to find ways to cause the suppression of the expression of the protein only in certain nerve cells, in order to improve our understanding of the basis of epilepsy and to create new possibilities for treating the disease,”
the researchers added.
Christopher Heise, Elham Taha, Luca Murru, Luisa Ponzoni, Angela Cattaneo, Fabrizia C. Guarnieri, Caterina Montani, Adele Mossa, Elena Vezzoli, Giulio Ippolito, Jonathan Zapata, Iliana Barrera, Alexey G. Ryazanov, James Cook, Michael Poe, Michael Rajesh Stephen, Maksym Kopanitsa, Roberta Benfante, Francesco Rusconi, Daniela Braida, Maura Francolini, Christopher G. Proud, Flavia Valtorta, Maria Passafaro, Mariaelvina Sala, Angela Bachi, Chiara Verpelli, Kobi Rosenblum, Carlo Sala
eEF2K/eEF2 Pathway Controls the Excitation/Inhibition Balance and Susceptibility to Epileptic Seizures
Cerebral Cortex, 2016; bhw075 DOI: 10.1093/cercor/bhw075
Image: A J Irving, Wellcome Images