Long-lasting auditory gating deficit accompanied by GABAB receptor dysfunction in the hippocampus after early-life limbic seizures in rats

In a previous study, we reported a rat model of early-life limbic seizures which resulted in a loss of GABAB receptor inhibition in the hippocampus. Since gating of auditory evoked potentials in the hippocampus (auditory gating) requires GABAB receptors and spatial behaviors depend on the hippocampus, we hypothesize that rats with early-life limbic seizures manifest deficits of auditory gating and spatial behaviors. Seizure rats were given a single injection of GABAB receptor antagonist CGP56999A (1-1.2 mg/kg i.p.) on postnatal day (PND) 15, which induced multiple limbic seizures in 8 h; control rats were given saline injection. When tested at 3-9 weeks after seizure/control treatment, seizure as compared to control rats showed no difference in finding a hidden platform in the water maze, but were deficient in learning and maintaining consecutive criterion performance in the 8-arm radial arm maze. Auditory gating, as measured by paired-click (conditioning followed by test click) average auditory evoked potentials in the hippocampus, revealed a significant difference between seizure rats and controls. Seizure as compared to control rats showed an increased ratio of the test to conditioning click response as adolescents (50 days old) or adults (70 days old). Heterosynaptic electric paired-pulse depression of hippocampal population excitatory postsynaptic potential in freely moving rats, a measure of hippocampal GABAB-receptor mediated inhibition, was decreased in seizure as compared to control rats. Seizure as compared to control rats showed increased locomotor activity in a novel open field for the first 10 min, and decreased activity at 15-60 min. However, auditory prepulse inhibition, a measure of sensorimotor gating, revealed no difference between seizure and control rats. In conclusion, early-life limbic seizures induced a long-lasting deficit in auditory gating, likely caused by GABAB receptor-mediated inhibition loss in the hippocampus. Auditory gating loss is a symptom of schizophrenia, and thus GABAB receptor inhibition loss in the hippocampus provides a mechanism linking early-life seizures to a psychiatric symptom.

► GABA-B receptor blockade resulted in limbic seizures in immature rats. ► Early-life seizures resulted in long-term behavioral changes. ► Seizure rats showed reduced auditory gating and GABA-B receptor function in the hippocampus. ► Seizure rats showed mild disruption in acquiring the spatial radial arm maze.