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The Journal of Neuroscience, October 19, 2005, 25(42):9649-9657; doi:10.1523/JNEUROSCI.2687-05.2005

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Neurobiology of Disease
Dysfunction of Synaptic Inhibition in Epilepsy Associated with Focal Cortical Dysplasia

Maria Elisa Calcagnotto,¹ Mercedes F. Paredes,^1,2 Tarik Tihan,³ Nicholas M. Barbaro,¹ and Scott C. Baraban^1,2

¹Epilepsy Research Laboratory, Department of Neurological Surgery, ²Graduate Program in Neuroscience, and ³Department of Pathology, University of California, San Francisco, San Francisco, California 94143

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.

Key words: dysplasia; epilepsy; human brain slices; inhibition; GABA; GAT

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Received June 29, 2005; revised August 19, 2005; accepted September 3, 2005.

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