Recurrent seizures cause immature brain injury and changes in GABA a receptor α1 and γ2 subunits.

ABSTRACT

OBJECTIVE: Recurrent seizures can cause brain damage and affect the cognitive outcome, particularly in developing children. We aimed to determine the effects of recurrent seizures on the expression of gamma-aminobutyric acid A receptor (GABAAR) α1 and γ2 subunit and neurodevelopment in immature rats. The role of the GABAAR agonist clonazepam and antagonist/partial agonist flumazenil in seizure-induced brain injury was also studied. METHODS: Recurrent seizures (RS) were induced by flurothyl inhalation in immature rats. Clonazepam (CZP) and flumazenil (FMZ) were administered to modulate GABAAR subunit expression in different experimental groups. Neurobehavioral changes and GABAAR α1 and γ2 subunit expression were studied. RESULTS: Inhalation of flurothyl for five days triggered RS and caused reflex delay, inability to adapt to new environments in adulthood, and deficits in long-term learning and memory ability in rats. Down-regulation of GABAAR α1 and γ2 subunits occurred after seizure onset and persisted for a long time. CZP treatment decreased the expression of GABAAR α1 and γ2 subunits and delayed neurodevelopment of the immature rats, whereas FMZ did not show any significant effects. CONCLUSIONS: Changes in GABAAR α1 and γ2 subunit expression and neurodevelopment were related to recurrent seizures and administration of CZP. Thus, GABAAR α1 and γ2 subunits likely play a significant role in the development of immature rats with RS and provide a novel target for therapeutic intervention.