Brain Advance Access published online on June 2, 2004
Brain, doi:10.1093/brain/awh181
© 2004 by Guarantors of Brain
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1 Dipartimento di Fisiologia Umana e Farmacologia ‘V. Erspamer’, Università degli Studi di Roma ‘La Sapienza’, Roma, Italy; IRCCS Neuromed, Pozzilli (Is), Italy
* To whom correspondence should be addressed. E-mail: massimo.avoli{at}mcgill.ca.
Patients with Taylor’s type focal cortical dysplasia (FCD) present with seizures that are often medically intractable. Here, we attempted to identify the cellular and pharmacological mechanisms responsible for this epileptogenic state by using field potential and K+-selective recordings in neocortical slices obtained from epileptic patients with FCD and, for purposes of comparison, with mesial temporal lobe epilepsy (MTLE), an epileptic disorder that, at least in the neocortex, is not characterized by any obvious structural aberration of neuronal networks. Spontaneous epileptiform activity was induced in vitro by applying 4-aminopyridine (4AP)-containing medium. Under these conditions, we could identify in FCD slices a close temporal relationship between ictal activity onset and the occurrence of slow interictal-like events that were mainly contributed by GABAA receptor activation. We also found that in FCD slices, pharmacological procedures capable of decreasing or increasing GABAA receptor function abolished or potentiated ictal discharges, respectively. In addition, the initiation of ictal events in FCD tissue coincided with the occurrence of GABAA receptor-dependent interictal events leading to [K+]o elevations that were larger than those seen during the interictal period. Finally, by testing the effects induced by baclofen on epileptiform events generated by FCD and MTLE slices, we discovered that the function of GABAB receptors (presumably located at presynaptic inhibitory terminals) was markedly decreased in FCD tissue. Thus, epileptiform synchronization leading to in vitro ictal activity in the human FCD tissue is initiated by a synchronizing mechanism that paradoxically relies on GABAA receptor activation causing sizeable increases in [K+]o. This mechanism may be facilitated by the decreased ability of GABAB receptors to control GABA release from interneuron terminals. Key Words:
baclofen; epileptiform synchronization; focal cortical dysplasia; GABA receptors; [K+]o homeostasis
Revised February 13, 2004
Accepted March 8, 2004
Article
GABAA receptor-dependent synchronization leads to ictogenesis in the human dysplastic cortex
2 INSERM U 109, Centre de Recherche P. Broca and Hôpital Sainte-Anne, Paris, France
3 Department of Epileptology, University of Bonn, Bonn, Germany
4 IRCCS Fondazione Santa Lucia, Roma, Italy
5 Montreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University, Montréal, Québec, Canada
6 Dipartimento di Fisiologia Umana e Farmacologia ‘V. Erspamer’, Università degli Studi di Roma ‘La Sapienza’, Roma, Italy; IRCCS Neuromed, Pozzilli (Is), Italy; Montreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University, Montréal, Québec, Canada; 3801 University Street, Montreal, QC, H3A 2B4 Canada
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