Increased number of GABA B receptors in the lethargic ( lh/lh) mouse model of absence epilepsy

Abstract

This study begins to explore 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 [ 3H]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 (4.2pmol/mg protein, n = 43 pairs, P < 0.02) than in +/+ mice (3.3 pmol/mg protein) in an age-dependent manner. Interestingly, the subject 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 (1–20 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 ([ 3H]glutamate binding) and to GABA A sites ([ 3H]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.