INCREASED NUMBER OF GABA(B) RECEPTORS IN THE LETHARGIC (LH/LH) MOUSE MODEL OF ABSENCE EPILEPSY

This study begins to explore possible mechanisms underlying the role of GABA(B) receptors in absence seizures in lethargic (lh/lh) mice. To test the hypothesis that alterations intrinsic to the GABA(B) receptor underlie enhanced synaptic activation of these receptors in absence seizures, we measured GABA-displaceable [H-3]baclofen binding to neocortical plasma membranes prepared from lh/lh and wild (+/+) age-matched congenic mice. The number (B(max)) of binding sites was significantly greater (20%) in lh/lh (4.2 pmol/mg protein, n = 43 pairs, P < 0.02) than in +/+ mice (3.3 pmol/mg protein) in an age-independent manner. Interestingly, the subset of lh/lh mice with greater seizure frequency (40-70 seizures/15 min, measured by bipolar electrodes implanted into neocortex; n = 11) had a significantly greater B(max) (P < 0.003) than the subset with lower seizure frequency (1-10 seizures/15 min; n = 11). The equilibrium dissociation constant (K(d)) Was unchanged (60 nM in both). The K(d) of both strains was inhibited to an equal degree by the nonhydrolysable GTP analogue 5'-guanylimido-diphosphate [Gpp(NH)p]. The increased number of GABA(B) binding sites was selective, because binding to NMDA sites ([H-3]glutamate binding) and to GABA(A) sites ([H-3]muscimol binding) was not significantly different in the two strains. These data suggest that the increased number of GABA(B) receptors in lh/lh mice underlies enhanced synaptic activation of these receptors. Together with evidence that GABA(B) receptor activation can produce disinhibition, our data support a role for GABA(B) receptors in the expression of absence seizures in lh/lh mice.