Dysfunction of synaptic inhibition in epilepsy associated with focal cortical dysplasia

Maria Elisa Calcagnotto, Mercedes F. Paredes, Tarik Tihan, Nicholas M. Barbaro, Scott C. Baraban

Research output: Contribution to journalArticle

112 Scopus citations

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 GABA A-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.

Original languageEnglish (US)
Pages (from-to)9649-9657
Number of pages9
JournalJournal of Neuroscience
Volume25
Issue number42
DOIs
StatePublished - Oct 19 2005

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Keywords

  • Dysplasia
  • Epilepsy
  • GABA
  • GAT
  • Human brain slices
  • Inhibition

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Calcagnotto, M. E., Paredes, M. F., Tihan, T., Barbaro, N. M., & Baraban, S. C. (2005). Dysfunction of synaptic inhibition in epilepsy associated with focal cortical dysplasia. Journal of Neuroscience, 25(42), 9649-9657. https://doi.org/10.1523/JNEUROSCI.2687-05.2005