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Volume 16, Number 13, Issue of July 1, 1996 pp. 4250-4260
Copyright ©1996 Society for Neuroscience

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

Received Feb. 5, 1996; revised April 12, 1996; accepted April 16, 1996.

Kurt Z. Haas¹, Ellen F. Sperber², Solomon L. Moshé^{1, 2, 3}, and Patric K. Stanton^{1, 2}

Departments of ¹ Neuroscience, ² Neurology, and ³ Pediatrics, Albert Einstein College of Medicine, Bronx, New York 10461-1602

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 (< 200 msec) was reduced after seizures, whereas late disinhibition remained intact. CGP 35348 blocked the early component of disinhibition in controls and, to a lesser extent, reduced disinhibition in KA slices. However, paired monosynaptic IPSPs recorded intracellularly showed no difference in disinhibition between groups. Our findings indicate that seizure-induced enhancement in dentate inhibition is caused, at least in part, by reduced GABA_B function in the polysynaptic recurrent inhibitory circuit, resulting in reduced disinhibition and heightened GABA release.

Key words: hippocampus; dentate gyrus; paired-pulse inhibition; GABA_B; disinhibition; presynaptic; autoreceptors; kainic acid; bicuculline; CGP 35348; epilepsy; seizures

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