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• Enhancement of GABAA-current run-down in the hippocampus occurs at the first spontaneous seizure

in a model of temporal lobe epilepsy

• Manuela Mazzuferia, Eleonora Palmac, Katiuscia Martinelloe, Francesca Maiolinod, Cristina Rosetic, Sergio Fucilec, Paolo F. Fabenef, Federica Schiof, Michele Pellitterif, Guenther Sperkg, Ricardo Miledih, Fabrizio Eusebic, and Michele Simonatoa, Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3180-5. Epub 2010 Jan 26.

• Keywords: GABAA receptor | pilocarpine rat | Xenopus oocytes

• Input author

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MANUSCRIPT Details

• Introduction/Aims

Nearly one third of patients with temporal lobe epilepsy (TLE) are refractory to treatment with current anti-epileptic drugs (AEDs), and must resort to surgical resection of the epileptic focus for relief. In order to design better treatments for these patients, it would be helpful to better understand the mechanisms involved in the process of epileptogenesis. An increase toward hyperexcitability due to a reduction in inhibition has been a generally proposed mechanism. More specifically, GABA current run-down has been shown to occur in epileptic tissue ablated during epilepsy surgery. It is unclear whether the run-down observed in human epileptic tissue occurred due to the seizures or was part of the epileptogenic process.

The aim of this paper was to determine the timing of this mechanism in the course of the disease progression.

• Method:

A commonly used model of temporal lobe epileptogenesis, the rat pilocarpine seizure model, was studied to determine the timing of GABA current run-down during the epileptogenic process—in the so called “silent period” between the epileptogenic insult and the first clinically detectable spontaneous seizure.

Video-EEG monitoring was used to determine the timing of the first spontaneous recurrent seizure (SRS), thus the onset of clinical epilepsy.

Animals were sacrificed at 24 hours (acute time point), 5 days (latency), following first spontaneous seizure (~9 days), 2 wks following first seizure (chronic phase), or 2 months following the first seizure (late chronic phase). Comparisons were made between tissue from epileptic animals at these time points and naïve tissue. A second control group was composed of “resistant” animals, which did not become epileptic following the epileptogenic insult.

Tissue was either 1) homogenized into membrane vesicles from cortex or hippocampal tissue and injected into xenopus oocytes or 2) prepared into coronal sections. Whole cell patch clamp was used on oocytes or cortical slices and GABA current run down was measured in response to exogenously released GABA.