Selective loss of early suppression in the dentate gyrus precedes kainic acid induced electrographic seizures

The role of inhibitory and facilitatory processes in the induction of seizures was studied in a kainic acid (KA) model of epilepsy. The dentate gyrus (DG) response to paired-pulse stimulation of the perforant path (PP) was monitored prior to and immediately following the initial KA induced afterdischarge (AD) in rats chronically prepared with stimulation recording electrodes. The subjects received a 1-h program of stimulation consisting of repeated sequences of pulse pairs at a short (20-30 ms), intermediate (45-90 ms), and long (200-300 ms) interpulse interval (IPIs). The stimulation program was administered both under control conditions and immediately following systemic injection of KA. During the control condition, stable suppression of population spike measures was obtained at the short (early phase) and long (late phase) IPIs, while facilitation was observed at the intermediate IPI. Administration of KA resulted in a progressive loss of suppression prior to the initial AD at the short IPI; neither facilitation nor the late phase of suppression were significantly affected. The early phase decreased further following the initial discharge. Since the early phase most likely reflects recurrent inhibition, these results provide evidence that inhibitory loss precedes the occurrence of KA induced AD, and that this inhibitory loss is increased further following the initial evoked AD. A use-dependent disinhibition is one possible explanation for the change in responsiveness that precedes the AD. This disinhibition could result from a depressed response at GABA-A receptors, an increased responsiveness at GABA-B receptors or possibly both.