Kainic Acid-Induced Seizures Enhance Dentate Gyrus Inhibition by Downregulation of GABAB Receptors

Seizures cause a persistent enhancement in dentate synaptic inhibition concurrent with, and possibly compensatory for, seizure-induced hippocampal hyperexcitability. To study this phenomenon, we evoked status epilepticus in rats with systemic kainic acid (KA), and 2 weeks later assessed granule cell inhibition with paired-pulse stimulation of the perforant path (PP) in vitro . Controls demonstrated three components of paired-pulse inhibition: early inhibition (10–30 msec), intermediate facilitation (30–120 msec), and late inhibition (120 msec to 120 sec). After seizures, inhibition in all components was enhanced significantly. The GABA A antagonist bicuculline blocked only early enhanced inhibition, demonstrating that both GABA A and GABA B postsynaptic receptors contribute to seizure-induced enhanced inhibition. In controls, the GABA B antagonist CGP 35348 increased both GABA A and GABA B responses in granule cells, suggesting that CGP 35348 acts presynaptically, blocking receptors that suppress GABA release. In contrast, slices from KA-treated rats were markedly less sensitive to CGP 35348. To test the hypothesis that GABA B receptors regulating GABA release are downregulated after seizures, we measured paired-pulse suppression of recurrent IPSPs, or disinhibition, using mossy fiber stimuli. Early disinhibition (