A new ‘MAP’?

In thinking about the link which could exist between the role of the protein originating from EFCH1 in cell mitosis and the involvement of this gene in juvenile myoclonic epilepsy, Thierry Grisar and Bernard Lakaye arrived at the following question: ‘And what if this protein acted on the cell division of neurons during the development of the nervous system?’

‘It was necessary to find a method to see if this protein intervened in the cell division of primary neurons, the neuroblasts, and if it had an effect on cortical development,’ explains Thierry Grisar. To do this they used the electroporation technique in utero, on rat embryos. This technique consists of applying an electrical field on the skull of a mouse embryo in utero, which enables the introduction into developing cortical neurons of either RNA inhibitors, which inhibit the expression of the EFHC1 gene, or a mutant version of this gene.

‘Laurence de Nijs, whose doctorate I am supervising, learnt this technique, under the wing of Professor Joseph Lo Turco, in the physiology and neurobiology laboratory at the University of Connecticut in the United States,’ underlines Bernard Lakaye. ‘During her stay there she was able to observe that when the protein’s activity is blocked, that disrupts neuron division and migration,’ continues Thierry Grisar.

According to Bernard Lakaye, the EFCH1 gene codes a protein which interacts with microtubules (MAP, for Microtubule-Associated Protein), fibres which make up the cytoskeleton and which play a predominant role in cell division and in neuronal migration over the course of brain development. This recent discovery was the subject of a publication (2) in Nature Neurosciences. ‘From the microtubules, the EFHC1 protein drives these two mechanisms. It is also important to note that this protein is not strongly expressed, which seems to indicate that it has a subtle yet capital role,’ adds Thierry Grisar.

From an idiopathic epilepsy to a lesional one

What does this present study offer in terms of knowledge of juvenile myoclonic epilepsy? ‘We suggest that henceforth this syndrome, up until now classed amongst idiopathic epilepsies, is considered as resulting from micro-dysgenesis, in other words from very discrete tiny lesions, due to subtle disorders of intracortical development,’ concludes Thierry Grisar.

Having up until now studied the effect of the inhibition of the EFHC1 gene on neuron development, the scientists would now like to refine their research by attempting to discover the link between different mutations of this gene, the presence of small lesions in the cortex and the hyperexcitability of the neurons. ‘In the next three years, I would like our team to be able to observe the behaviour of rats whose EFHC1 gene has been mutated in utero and who have reached adolescence,’ says the neurologist, looking ahead. ‘These experiments should allow us to verify that light lesions of the cortical circuit are capable of producing a heightened excitability of neurons in a zone of the cortex.’ Such research work could in effect permit the scientific world to take a large step in understanding better and to thus treating these illnesses which are known as epilepsies, pathologies which some of the world’s greatest figures are thought to have suffered from, such as Julius Caesar, Vincent Van Gogh, Ludwig van Beethoven, Napoleon Bonaparte or Alfred Nobel !

(2) de Nijs, L., Léon, C., Nguyen, L., Loturco, J.J., Delgado-Escueta, A.V., Grisar, T., Lakaye, B., 2009. EFHC1 interacts with microtubules to regulate cell division and cortical development, Nat. Neurosci. Published online 6 September 2009.