Suppression of epileptiform activity by GABA(B) receptors in wild type and weaver hippocampus 'in vitro'.
Inhibition by GABA(B) receptors comprises activation of K(+) conductance and inhibition of Ca(2+) conductance, thereby reducing action potential dependent transmitter release and silencing neuronal activity. We compared epileptiform activity and its inhibition by the activation of GABA(B) receptors in homozygous weaver (wv/wv) and wild type (+/+) CA3 neurons disinhibited by GABA(A) receptor blockade. In wv/wv mice GABA(B) receptors have lost their ability to activate K(+) conductance (J. Neurosci. 18 (1998) 4001). Spontaneous synchronous burst discharges in elevated [K(+)](o) displayed only subtle differences in +/+ and wv/wv slices, except that the GABA(B) receptor agonist R-baclofen in low concentration (0.1 microM) strongly reduced the frequency of synchronous bursts in +/+ CA3 neurons, but not in wv/wv CA3 neurons. A high affinity GABA(B) antagonist, CGP55845A (0.5 microM) promoted the incidence of bursts in low [K(+)](o). Concentration dependence of the reduction of evoked EPSCs was identical in wv/wv and +/+ neurons (IC(50)=0.3 microM). Amplitudes of evoked IPSCs were reduced by 0.01 microM R-baclofen in +/+, but not in wv/wv CA3 neurons. The effect of the low concentration was abolished by Ba(2+), which is known to block Kir conductance. The data suggest that activation of Kir conductance is important for the control of GABA release by GABA(B) autoreceptors in the CA3 network. We conclude that the loss of a contribution of Kir conductance to GABA(B) receptor-mediated autoinhibition reduces the inclination towards spontaneous bursts of wv/wv CA3 pyramidal neurons.
Yanovsky
Yevgenij
Y
Institut für Physiologie und Pathophysiologie, Universität Heidelberg, Im Neuenheimer Feld 326, D-69120, Heidelberg, Germany.
Misgeld
Ulrich
U
D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D004827:Epilepsy / Q000517:prevention & control*; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D008818:Mice, Neurologic Mutants; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D018080:Receptors, GABA-B / Q000502:physiology*
D018755:GABA Agonists; D018080:Receptors, GABA-B; D001418:Baclofen; D001640:Bicuculline