CV Science

Laurent Aniksztejn Deregulation of glutamate homeostasis in the developing brain: Relevance to early epileptic encephalopathy.

Course and current status

Laurent Aniksztejn (Neurophysiologist, Electrophysiologist) has been recruited at INSERM in 1992. He has done his career in Y. Ben-Ari’s laboratory first in Paris then in Marseille. He has worked on several subjects mostly performed in the hippocampus including: i) the release of zinc by hippocampal mossy fibers (during its master) where he described, in vivo using the push-pull technique, that the selective stimulation of these fibers released Zn²⁺, ii) mechanism of long-term potentiation in CA1 region of the hippocampus which was the subject of his thesis. He described three different characteristics of LTP: -LTP is not associated with a persistent increase of glutamate release (experiments performed in vivo with the push-pull technique and combined with electrophysiological recordings); - LTP can be generated via the activation of voltage dependent calcium channels and independently to NMDA-Rs. Moreover, he described for the first time the existence of a cross-talk between metabotropic glutamate receptors and NMDA-Rs via the protein kinase C facilitating the reach of threshold for LTP induction. After his PhD, he pursued some experiments on LTP and described mechanisms necessary to the induce LTP of NMDA-Rs. Then, he completed his electrophysiological training in Pierre Drapeau’s laboratory (Montreal, Canada) between 1995 and 1997 on two different subjects which were dedicated to the regulation of mechanosensitive cationic channels by tyrosine kinase in leech and to the development of neuromuscular junction in zebrafish. Thanks to his PhD and postdoctoral position, he gained experiences in patch-clamp recordings (whole-cell, inside-out; outside-out) and particularly with single channel analysis. When he came back in France, he decided to work on morphological and electrophysiological development of the hippocampus in association with Alfonso Represa. They described: i) the existence of a paracrine form of communication between developing neurons before the formation of synapses and that implicate essentially GABA but not glutamate; ii) that this mode of communication played important role for neuronal migration; iii) that functional GABAergic synapses formed prior to glutamatergic synapses; iv) that cell-surface glutamate transporters operated prior to GABA transporters. These last findings were at the origin of the subject he has developed since few years which is dedicated to the role of glutamate transporters in developing brain. This subject was the origin of his interest in neonatal epilepsy notably after, the description, in collaboration of Mathieu Milh, a neuropediatrician, that dysfunction of glutamate transporters caused in rat pups an electrographic pattern highly reminiscent to some early onset epileptic encephalopathy. Now, he wants to continue this subject  in order to understand how this dysfunction causes the pathological activity and to determine if glutamate transporters are included in the sequence of events leading reported inactivation of glutamine synthetase and of mitochondrial glutamate carrier to this severe disease.

Scientific summary

Early epileptic encephalopathy with suppression burst (EEESB) (Othahara syndrome, early myoclonic encephalopathy) is a group of rare, severe and refractory epilepsies that begin during the 3 first month of life . They are frequently associated with a discontinuous Electro-Encephalographic (EEG) pattern with recurrent paroxysmal burst alternating with silent period: the so called Suppression-Burst pattern (SB) and also partial seizures.The pathophysiological bases of EEESB are still misunderstood because of great heterogeneous etiologies including cortical malformations, metabolic disorders and diverse genetic defects suggesting that these diseases may involve different cellular mechanisms.

Cell-surface glutamate transporters play major role in glutamate homeostasis in the brain, binding and transporting glutamate from extracellular to intracellular space thus preventing glutamate accumulation in the extracellular space. We have previously found that a deficit in glutamate uptake following their inhibition by DL-TBOA generated in vivo, in rat pups a suppression burst EEG pattern and partial seizures rising the possibility that glutamate transporters could dysfunction in EEESB. Interestingly, we also found that DL-TBOA generated the same pattern of activity in vitro, in both neocortical and hippocampal slices  that we referred as recurrent recurrent epileptic like paroxysmal burst (RELPB).As observed with the in-vivo experiments, RELPB were fully blocked or prevented by NMDA-Rs antagonists suggesting that RELPB in vitro and epileptical activity in vivo share similar mechanisms and implicate a circuit that is present in cortical slices. Therefore, studying the processes involved in the generation of RELPB may be relevant to understand the mechanisms leading to the generation of the pathological activities observed in the newborn rat. Our works aim to  further investigate, using the TBOA model, the cellular mechanisms leading glutamate transporters dysfunction to generate this specific type of epileptical activity. Moreover, we also investigate if there is any relation between glial glutamate transporters efficiency and the catabolism of glutamate in astrocytes, knowing that inactivation of some proteins involved in this catabolism due to gene mutations have been reported in some neonates suffering from early epileptic encephalopathy.