Biomedical subjects

Jacques Louvel

Publications and source records attributed to Jacques Louvel.

7 recordsLinked to original sources

PubMed2005

Cellular and molecular mechanisms of epilepsy in the human brain.

Animal models have provided invaluable data for identifying the pathogenesis of epileptic disorders. Clearly, the relevance of these experimental findings would be strengthened by the demonstration that similar fundamental mechanisms are at work in the human epileptic brain. Epilepsy surgery has indeed opened the possibility to directly study the functional properties of human brain tissue in vitro, and to analyze the mechanisms underlying seizures and epileptogenesis. Here, we summarize the findings obtained over the last 40 years from electrophysiological, histochemical and molecular experiments made with the human brain tissue. In particular, this review will focus on (i) the synaptic and non-synaptic properties of neocortical neurons along with their ability to produce synchronous activity; (ii) the anatomical and functional alterations that characterize limbic structures in patients presenting with mesial temporal lobe epilepsy; (iii) the issue of antiepileptic drug action and resistance; and (iv) the pathophysiology of seizure genesis in Taylor's type focal cortical dysplasia. Finally, we will address some of the problems that are inherent to this type of experimental approach, in particular the lack of proper controls and possible strategies to obviate this limitation.

Animals↗

PubMed2004

Glyceraldehyde-3-phosphate dehydrogenase is a GABAA receptor kinase linking glycolysis to neuronal inhibition.

Protein phosphorylation is crucial for regulating synaptic transmission. We describe a novel mechanism for the phosphorylation of the GABA(A) receptor, which mediates fast inhibition in the brain. A protein copurified and coimmunoprecipitated with the phosphorylated receptor alpha1 subunit; this receptor-associated protein was identified by purification and microsequencing as the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Molecular constructs demonstrated that GAPDH directly phosphorylates the long intracellular loop of GABA(A) receptor alpha1 subunit at identified serine and threonine residues. GAPDH and the alpha1 subunit were found to be colocalized at the neuronal plasma membrane. In keeping with the GAPDH/GABA(A) receptor molecular association, glycolytic ATP produced locally at plasma membranes was consumed for this alpha1 subunit phosphorylation, possibly within a single macrocomplex. The membrane-attached GAPDH is thus a dual-purpose enzyme, a glycolytic dehydrogenase, and a receptor-associated kinase. In acutely dissociated cortical neurons, the rundown of the GABA(A) responses was essentially attributable to a Mg(2+)-dependent phosphatase activity, which was sensitive to vanadate but insensitive to okadaic acid or fluoride. Rundown was significantly reduced by the addition of GAPDH or its reduced cofactor NADH and nearly abolished by the addition of its substrate glyceraldehyde-3-phosphate (G3P). The prevention of rundown by G3P was abolished by iodoacetamide, an inhibitor of the dehydrogenase activity of GAPDH, indicating that the GABA(A) responses are maintained by a glycolysis-dependent phosphorylation. Our results provide a molecular mechanism for the direct involvement of glycolysis in neurotransmission.

Adenosine Diphosphate↗

PubMed2003

Epileptiform synchronization in the human dysplastic cortex.

Taylor's focal cortical dysplasia corresponds to a localized disruption of the normal cortical lamination with an excess of large, aberrant cells. Sustained epileptic discharges originate from the dysplastic neocortex and this tissue retains sufficient connectivity for expressing seizure abnormalities. In this brief review, we summarize the findings obtained by analyzing surgically-resected human tissue with focal cortical dysplasia that was maintained in vitro in a brain slice preparation. These data have been compared with those obtained from human cortex with normal structural organization; such tissue was available from patients undergoing surgery for a variety of neurological disorders, most often for mesial temporal lobe epilepsy. These studies have shown that: (i). slices obtained from focal cortical dysplastic tissue have an intrinsic ability to generate ictal-like epileptiform events when challenged with the convulsant drug 4-aminopyridine; (ii). 4-aminopyridine-induced ictal discharges are not seen in neocortical slices obtained from neocortical samples with no or minimal structural lesion; (iii). these ictal discharges are caused by the activation of excitatory amino acid receptors, and in particular those of the N-methyl-D aspartate type; (iv). focal cortical dysplastic tissue also generates synchronous potentials that are mainly contributed by GABA(A) receptor-mediated conductances.

4-Aminopyridine↗

PubMed2002

Event-related potentials recorded from the cingulate gyrus during attentional tasks: a study in patients with implanted electrodes.

Recent neuroimaging data suggests that the cingulate gyrus is involved in a variety of cognitive tasks. In this study sensory field potentials were directly recorded from the cingulate gyrus in order to investigate its implication in attentional processes associated or not with a motor task. Evoked potentials recordings were performed in 29 epileptic patients with multilead electrodes implanted for presurgical evaluation, who agreed to participate in an experimental protocol consisting of a series of paradigms designed using a warning auditory tone, two distinct visual patterns and various attentional, memory, motor and decisional tasks. Our data shows that evoked potentials could be recorded from various parts of the cingulate gyrus. The inclusion of an instruction in the experimental paradigm resulted in an increase in the amplitude of the late, intrinsic component of the visual evoked potential culminating at about 450 ms. Several variations of response patterns across individuals were identified. We conclude that the cingulate gyrus appears to be a multimodal area involved in several types of cognitive activity, including attention. Variations in response patterns are probably related to differences in the strategy adopted by each subject when faced with a particular cognitive task.

Adult↗

PubMed2002

Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro.

Seizures in patients presenting with mesial temporal lobe epilepsy result from the interaction among neuronal networks in limbic structures such as the hippocampus, amygdala and entorhinal cortex. Mesial temporal lobe epilepsy, one of the most common forms of partial epilepsy in adulthood, is generally accompanied by a pattern of brain damage known as mesial temporal sclerosis. Limbic seizures can be mimicked in vitro using preparations of combined hippocampus-entorhinal cortex slices perfused with artificial cerebrospinal fluid containing convulsants or nominally zero Mg(2+), in order to produce epileptiform synchronization. Here, we summarize experimental evidence obtained in such slices from rodents. These data indicate that in control animals: (i) prolonged, NMDA receptor-dependent epileptiform discharges, resembling electrographic limbic seizures, originate in the entorhinal cortex from where they propagate to the hippocampus via the perforant path-dentate gyrus route; (ii) the initiation and maintenance of these ictal discharges is paradoxically contributed by GABA (mainly type A) receptor-mediated mechanisms; and (iii) CA3 outputs, which relay a continuous pattern of interictal discharge at approximately 1Hz, control rather than sustain ictal discharge generation in entorhinal cortex. Recent work indicates that such a control is weakened in the pilocarpine model of epilepsy (presumably as a result of CA3 cell damage). In addition, in these experiments electrographic seizure activity spreads directly to the CA1-subiculum regions through the temporoammonic pathway. Studies reviewed here indicate that these changes in network interactions, along with other mechanisms of synaptic plasticity (e.g. axonal sprouting, decreased activation of interneurons, upregulation of bursting neurons) can confer to the epileptic, damaged limbic system, the ability to produce recurrent limbic seizures as seen in patients with mesial temporal lobe epilepsy.

4-Aminopyridine↗

PubMed2002

Masking synchronous GABA-mediated potentials controls limbic seizures.

PURPOSE: We determined how CA3-driven interictal discharges block ictal activity generated in the entorhinal cortex during bath application of 4-aminopyridine (4AP, 50 microM). METHODS: Field potential and [K+]o recordings were obtained from mouse combined hippocampus-entorhinal cortex slices maintained in vitro. RESULTS: 4AP induced N-methyl-d-aspartate (NMDA) receptor-dependent ictal discharges that originated in the entorhinal cortex, disappeared over time, but were reestablished by cutting the Schaffer collateral (n = 20) or by depressing CA3 network excitability with local application of glutamatergic receptor antagonists (n = 5). In addition, two types of interictal activity occurred throughout the experiment. The first type was CA3 driven and was abolished by a non-NMDA glutamatergic receptor antagonist. The second type was largely contributed by gamma-aminobutyric acid type A (GABAA) receptor-mediated conductances and persisted during blockade of glutamatergic transmission. The absence of CA3-driven interictal discharges in the entorhinal cortex after Schaffer collateral cut facilitated the GABA-mediated interictal potentials that corresponded to large [K+]o elevations and played a role in ictal discharge initiation. Accordingly, ictal discharges along with GABA-mediated interictal potentials disappeared during GABAA-receptor blockade (n = 7) or activation of mu-opioid receptors that inhibit GABA release (n = 4). CONCLUSIONS: Our findings suggest that CA3-driven interictal events restrain ictal discharge generation in the entorhinal cortex by modulating the size of interictal GABA-mediated potentials that lead to large [K+]o elevations capable of initiating ictal discharges in this structure.

4-Aminopyridine↗

PubMed2002

Epileptiform synchronization and GABA(B) receptor antagonism in the juvenile rat hippocampus.

The GABA(B) receptor agonist baclofen enhances the epileptiform activity induced by 4-aminopyridine (4AP) in juvenile rat hippocampal slices. In this study, we used a similar experimental approach (i.e., field potential, intracellular, and [K+]o recordings in the CA3 area of slices obtained from 15-23-day-old rats) to establish whether antagonizing GABA(B) receptors could exert opposite (presumably anticonvulsant) effects. Bath application of 4AP (50 microM) induced spontaneous interictal and ictal discharges along with synchronous GABA receptor-mediated potentials. All types of 4AP-induced synchronous activity occurred more frequently during application of the GABA(B) receptor antagonist p3-amino-propyl,p-diethoxymethylphosphonic acid (CGP 35348) (0.1-1 mM; EC50 = 0.25 mM). Moreover, CGP 35348 augmented the frequency and, to a lesser extent, the duration of the asynchronous synaptic activity recorded intracellularly from CA3 pyramids (n = 19). In medium containing 4AP + ionotropic glutamatergic antagonists (which abolished interictal and ictal activity), CGP 35348 prolonged both GABA-receptor-mediated field potentials and the accompanying intracellular long-lasting depolarizations without modifying their rate (n = 12). The transient elevations in [K+]o associated with GABA receptor-mediated potentials in 4AP-containing medium (n = 7 slices) became larger during CGP 35348 application. Similar findings were obtained when CGP 35348 was applied to medium containing 4AP + ionotropic glutamatergic antagonists (n = 6). Thus, the effect of CGP 35348 on 4AP-induced epileptiform activity is not anticonvulsant and to some extent similar to what was reported in this model during GABA(B) receptor activation. We propose that the facilitation of ictal activity by CGP 35348 is mainly caused by the blockade of presynaptic GABA(B) receptor, leading to an increase in GABA release and subsequent larger [K+]o elevations.

Action Potentials↗