Increased number of GABAB receptors in the lethargic (lh/lh) mouse model of absence epilepsy.
This study begins to explore possible mechanisms underlying the role of GABAB receptors in absence seizures in lethargic (lh/lh) mice. To test the hypothesis that alterations intrinsic to the GABAB 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 (Bmax) 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 Bmax (P < 0.003) than the subset with lower seizure frequency (1-10 seizures/15 min; n = 11). The equilibrium dissociation constant (Kd) was unchanged (60 nM in both). The Kd of both strains was inhibited to an equal degree by the nonhydrolysable GTP analogue 5'-guanylimido-diphosphate [Gpp(NH)p]. The increased number of GABAB binding sites was selective, because binding to NMDA sites ([3H]glutamate binding) and to GABAA sites ([3H]muscimol binding) was not significantly different in the two strains. These data suggest that the increased number of GABAB receptors in lh/lh mice underlies enhanced synaptic activation of these receptors. Together with evidence that GABAB receptor activation can produce disinhibition, our data support a role for GABAB receptors in the expression of absence seizures in lh/lh mice.
Department of Medicine (Neurology), Duke University, Durham, NC.
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FH
Lin
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Cao
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Hosford
D000818:Animals; D001418:Baclofen / Q000378:metabolism; D015415:Biomarkers / Q000737:chemistry; D004195:Disease Models, Animal; D004832:Epilepsy, Absence / Q000378:metabolism*; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015203:Reproducibility of Results
D015415:Biomarkers; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D001418:Baclofen