Purpose: The inhibition of cholesterol synthesis with AY-9944 (AY) results in chronic recurrent atypical absence seizures in rodents. We hypothesized that cholesterol inhibition during the course of creating the AY model of atypical absence seizures results in an alteration of the entry of gamma-aminobutyric acid (GABA)(A) and GABA(B) receptors into lipid rafts that contributes to epileptogenesis in this model.
Methods: The cholesterol synthesis inhibitor AY (7.5 mg/kg) was administered on postnatal day (P) 2, P8, P14, and P20 in Long-Evans hooded rats. The incorporation of GABA(A) and GABA(B) receptor proteins into lipid rafts of the brain was then determined.
Results: AY produced a shift of both GABA(A) and GABA(B) receptors in the examined detergent-resistant membranes (DRMs) and the soluble fractions. The percentage of the GABA(A) and GABA(B) receptors that shifted out of the DRMs varied between 17% and 50%, but the proportion of receptors in DRMs were decreased to levels around that of P5 animals or even lower. The shift observed in the AY-treated versus control animals was statistically significant (p < 0.01) for both GABA(A) and GABA(B) receptors.
Conclusion: Cholesterol synthesis inhibition during rat brain development that is induced by AY leads to chronic atypical absence seizures and is associated with an alteration of GABA(A) and GABA(B) receptor proteins within lipid rafts. These data suggest a novel avenue of investigation into the epileptogenesis of experimental chronic atypical absence seizures.
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