Abstracts

The immature brain is more susceptible to seizures than the adult brain. However, the immature brain appears to be relatively resistant to seizure-induced pathological and neurophysiologic changes compared to the adult brain. The aim here is to investigate long-term alteration of synaptic transmission and excitability in the hippocampus in vivo after a new model of seizures induced by a systemic GABA[sub]B[/sub] receptor antagonist in the immature rat. Pups were given CGP56999A 1 mg/kg i.p. on postnatal day 14 and 16 to induce behavioral seizures. GABA[sub]B[/sub] receptor antagonists including CGP56999A have been shown to induce limbic and convulsive seizures in adult rats (Leung et al, Epilepsia 2005; 46:203). About 30 days after seizures, electrophysiology in the hippocampus was studied under urethane anesthesia. Laminar field potentials were recorded by 16-channel silicon probes in CA1 and dentate gyrus (DG), in response to paired-pulse stimulation of CA3 and medial perforant path, and analyzed as current source density. Population excitatory postsynaptic potentials at the dendrites and population spikes (PS) at the cell layer. Paired-pulse inhibition (PPI) is defined as the suppression of the 2^nd PS with respect to the 1^st PS. Whether PPI was affected by GABA[sub]B[/sub] receptor antagonist CGP35348, injected intracerebroventricularly (i.c.v.), was tested. CGP56999A i.p. injection resulted in seizures in rat pups manifested as episodic immobility, wet-dog shakes, running, mouth automatisms, focal forelimb clonus, squeaks, rearing, falling and tonic-clonic convulsions involving 4 limbs followed by postictal immobility. Myoclonic jerks were observed and elicited by auditory stimulation. Thirty days after seizures, PPI in CA1 evoked by CA3 stimulation was significantly decreased (PS2 was larger then PS1) at 150 to 400 ms interpulse intervals (IPIs) in seizure rats as compared to controls (P [lt] 0.05, ANOVA with posthoc test). In the DG, PPI at 400ms IPI was decreased significantly in seizure rats as compared to controls (P [lt] 0.05). GABA[sub]B [/sub]receptor antagonist CGP35348 i.c.v decreased PPI at 200 and 400 ms IPIs in CA1 in both seizure and control rats, and significantly increased PPI in the DG in seizure rats (P [lt] 0.01) but not in controls. Early-life seizures induced by GABA[sub]B[/sub] receptor blockade resulted in a long-term decrease of late paired-pulse inhibition in CA1 and DG, suggesting a long-lasting decrease of GABA[sub]B[/sub] receptor mediated inhibition in the hippocampus. Seizures induced by GABA[sub]B[/sub] receptor blockade may provide a useful model for studying the consequence of early-life seizures. (Supported by CIHR MOP-64433 and a Savoy Foundation studentship to ML Tsai.)