title: Dysfunction of synaptic inhibition in epilepsy associated with focal cortical dysplasia.
abstract: Focal cortical dysplasia (FCD) is a common and important cause of medically intractable epilepsy. In patients with temporal lobe epilepsy and in several animal models, compromised neuronal inhibition, mediated by GABA, contributes to seizure genesis. Although reduction in GABAergic interneuron density has been reported in FCD tissue samples, there is little available information on the resulting physiological changes in synaptic inhibition and the potential contribution of these changes to epileptogenesis in the dysplastic human brain. Using visualized whole-cell patch-clamp recordings from identified neurons in tissue slices obtained from patients with FCD, we demonstrate that GABAA-receptor-mediated inhibition is substantially altered in regions of dysplasia. These alterations include a significant reduction in IPSC frequency and a potentially compensatory decrease in transporter-mediated GABA reuptake function; the latter is marked by a significant increase in the decay-time constant for evoked and spontaneous IPSCs and a lack of effect of the GABA transport-inhibitor 1-[2([(diphenylmethylene)imino]oxy)ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride on IPSC kinetics. Immunohistochemical staining revealed a scattering of GABAergic interneurons across dysplastic cortex and striking reductions in GABA transporter expression. Together, these results suggest that profound alterations in GABA-mediated synaptic inhibition play an essential role in the process of epileptogenesis in patients with FCD.
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, California 94143, USA.
authors.forename: Maria Elisa
authors.initials: ME
authors.lastname: Calcagnotto
authors.forename: Mercedes F
authors.initials: MF
authors.lastname: Paredes
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Barbaro
authors.forename: Scott C
authors.initials: SC
authors.lastname: Baraban
mesh_terms: D000293:Adolescent; D000328:Adult; D004827:Epilepsy / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D019579:Neocortex / Q000473:pathology* / Q000502:physiology*; D009433:Neural Inhibition / Q000502:physiology*; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*