Diminished presynaptic GABA(B) receptor function in the neocortex of a genetic model of absence epilepsy.

Changes in GABA(B) receptor subunit expression have been recently reported in the neocortex of epileptic WAG/Rij rats that are genetically prone to experience absence seizures. These alterations may lead to hyperexcitability by downregulating the function of presynaptic GABA(B) receptors in neocortical networks as suggested by a reduction in paired-pulse depression. Here, we tested further this hypothesis by analyzing the effects induced by the GABA(B) receptor agonist baclofen (0.1-10 microM) on the inhibitory events recorded in vitro from neocortical slices obtained from epileptic (>180 day-old) WAG/Rij and age-matched, non-epileptic control (NEC) rats. We found that higher doses of baclofen were required to depress pharmacologically isolated, stimulus-induced IPSPs generated by WAG/Rij neurons as compared to NEC. We also obtained similar evidence by comparing the effects of baclofen on the rate of occurrence of synchronous GABAergic events recorded by WAG/Rij and NEC neocortical slices treated with 4-aminopyridine + glutamatergic receptor antagonists. In conclusion, these data highlight a decreased function of presynaptic GABA(B) receptors in the WAG/Rij rat neocortex. We propose that this alteration may contribute to neocortical hyperexcitability and thus to absence seizures.