Epileptogenesis and enhanced prepulse inhibition in GABA(B1)-deficient mice

The recent cloning of two GABA(B) receptor subunits, GABA(B1) and GABA(B2), has raised the possibility that differences in GABA(B) receptor subunit co mposition may give rise to pharmacologically or functionally distinct recep tors. If present, such molecular diversity could permit the selective targe ting of GABA(B) receptor subtypes specifically involved in pathologies such as drug addiction, spasticity, pain, and epilepsy. To address these issues we have developed a GABA(B1) subunit knockout mouse using gene targeting t echniques. In the brains of GABA(B1) null mice, all pre- and postsynaptic G ABA(B) receptor function was absent demonstrating that the GABA(B1) subunit is essential for all GABA(B) receptor-mediated mechanisms. Despite this, G ABA(B1) null mice appeared normal at birth, although by postnatal week four their growth was retarded and they developed a generalized epilepsy that r esulted in premature death. In addition, GABA(B1) heterozygote animals show ed enhanced prepulse inhibition responses compared to littermate controls, suggesting that GABA(B1) deficient mice exhibit increased sensorimotor gati ng mechanisms. These data suggest that GABA(B) receptor antagonists may be of benefit in the treatment of psychiatric and neurological disorders in wh ich attentional processing is impaired.