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

Abstract

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 (K A), 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 K A-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 (Ͻ 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 K A 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.

Status Epilepticus-Induced Somatostatinergic Hilar Interneuron Degeneration Is Regulated by Striatal Enriched Protein Tyrosine Phosphatase

“…Thus, the selective loss of inhibitory input to the GCL has been suggested to enhance hippocampal excitability. However, it should also be noted that a number of studies have found that inhibitory drive to the GCL is enhanced in animal models of TLE (Tuff et al, 1983;Haas et al, 1996;Buckmaster and Dudek, 1997).…”

Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats

“…We further asked whether postnatal LPS treatment could generate a comparable susceptibility to a different chemoconvulsant that also causes a well defined pattern of neuronal damage in the hippocampus, yet through an entirely different mechanism of action as LI-PILO and PTZ. Male rats received either saline or LPS (100 g/kg) on P14 as described above (n ϭ 6 -7/group), and then 2 months later received 15 mg/kg KA intraperitoneally (Haas et al, 1996). Seizure onset time was recorded as defined above for LI-PILO, and pentobarbital (20 mg/kg, i.p.)…”

β-Estradiol Increases Dentate Gyrus Inhibition in Female Rats via Augmentation of Hilar Neuropeptide Y

“…Interstimulus intervals between the paired stimuli ranged from 10 to 1000 ms, corresponding to frequencies of 100 to 1 Hz. The paired stimuli were repeatedly applied to the same tissue every 30 s. This interval ensured full recovery between stimuli so that the response to one stimulus pair was not affected by the previous stimulus pair (Haas et al, 1996). Extracellular evoked responses (population spikes) were recorded using glass recording micropipette (1-5 M⍀) filled with 2 M NaCl placed in the middle third of the external blade of the dentate gyrus granule cell layer (stratum granulosum).…”

“…The paired-pulse curve was constructed by calculating population spike amplitude ratio (R 2 /R 1 ) at increasing interstimulus intervals. The curve consisted of three components (Haas et al, 1996;Velíšek and Velíšková, 2002) referred to here as (1) early inhibition (10 -50 ms), (2) intermediate facilitation (70 -125 ms), and (3) late inhibition (150 -1000 ms). Slices from OVX females treated with four daily doses of ␤-estradiol (2 g/rat; n ϭ 22) displayed significant enhancement of late paired-pulse inhibition at interstimulus intervals 125-1000 ms compared with slices from OVX controls (n ϭ 22) receiving oil (two-way ANOVA; main effect of treatment, F (1,42) ϭ 15.871; *p Ͻ 0.001).…”