Down-regulation of gephyrin and GABAA receptor subunits during epileptogenesis in the CA1 region of hippocampus

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SummaryPurposeEpileptogenesis is the process by which a brain becomes hyperexcitable and capable of generating recurrent spontaneous seizures. In humans, it has been hypothesized that following a brain insult there are a number of molecular and cellular changes that underlie the development of spontaneous seizures. Studies in animal models have shown that an injured brain may develop epileptiform activity before appearance of epileptic seizures and that the pathophysiology accompanying spontaneous seizures is associated with a dysfunction of γ-aminobutyric acid (GABA)ergic neurotransmission. Here, we analyzed the effects of status epilepticus on the expression of GABAA receptors (GABAARs) and scaffolding proteins involved in the regulation of GABAAR trafficking and anchoring.MethodsWestern blot analysis was used to determine the levels of proteins involved in GABAAR trafficking and anchoring in adult rats subjected to pilocarpine-induced status epilepticus (SE) and controls. Cell surface biotinylation using a cell membrane–impermeable reagent was used to assay for changes in the expression of receptors at the plasma membrane. Finally, immunoprecipitation experiments were used to evaluate the composition of GABAARs. We examined for a correlation between total GABAAR subunit expression, plasma membrane expression, and receptor composition.Key FindingsAnalysis of tissue samples from the CA1 region of hippocampus show that SE promotes a loss of GABAAR subunits and of the scaffolding proteins associated with them. We also found a decrease in the levels of receptors located at the plasma membrane and alterations in GABAAR composition.SignificanceThe changes in protein expression of GABAARs and scaffolding proteins detected in these studies provide a potential mechanism to explain the deficits in GABAergic neurotransmission observed during the epileptogenic period. Our current observations represent an additional step toward the elucidation of the molecular mechanisms underlying GABAAR dysfunction during epileptogenesis.

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