Carbenoxolone impairs LTP and blocks NMDA receptors in murine hippocampus

Effects of the gap junction blocker carbenoxolone (CBX) on tetanus- and taurine-induced long-term potentiation (LTP) were studied on Schaffer collateral-CA1 field excitatory postsynaptic potentials (fEPSPs) in mouse hippocampal slices. Preincubation with 10 microM CBX reduced the amount of LTP induced by weak theta-burst stimulation (TBS) or a single train of stimuli (HFS; 1s at 100 Hz), but did not affect LTP induced by 30-min perfusion with 10 mM taurine. Incubation with 50-100 microM CBX 15 min before HFS or TBS abolished tetanus-induced LTP. At 100 microM CBX, the concentration that is used for the blockade of gap junctions in vitro, a long-lasting depression of fEPSPs was observed which persisted under the blockade of NMDA receptors, and receptors for corticosteroids. A similar depression was produced by the CBX inactive analogue glycyrrhizic acid and the broad spectrum calcium channel antagonist ruthenium red. Whole-cell patch-clamp recordings from acutely isolated CA1 pyramidal neurons showed that CBX exerts a selective dose-dependent inhibition of NMDA-evoked currents with an IC(50)=104 microM. Thus the widely used gap junction uncoupler CBX acts as an antagonist at NMDA receptors and consequently impairs the induction of LTP.