5b (novel blocker of converse look ASICs) has little effect on inward GABAergic currents in  HEPES 10' solution. In the same series of experiments during each sweep evoked PSCs were recorded below their reversal potential as inward currents ( a ), and above the reversal potential, as outward ones ( b ). Superimposed traces of original current traces (averages of 10 sequential PSCs) before (solid lines) and after (dotted lines) 5b (1 ¼M) application are shown on the right panel, summary graphs ( n = 5) are shown on the left panel. PSC-amplitudes were normalized to control values (average of 20 PSCs preceding drug application).

It may be reasonably assumed, that if synaptic transmission is affected by a chemical via a purely presynaptic mechanism, similar changes of postsynaptic currents recorded below and above PSC reversal potential, would be expected. We converse all star found, however, that while GABAergic PSCs, recorded below their reversal potential as inward currents, are suppressed by all the employed ASIC blockers, in the same cells the suppression of outward currents was statistically insignificant. These results imply that the effects of blockers in our experiments are converse all stars at least partially postsynaptic.

Lack of substantial direct involvement of ASICs in PSCs generation in our experiments can be also supported by comparing the possible relative contribution of ASIC current to total synaptic current. Based on the results of our experiments with application of bicuculline alone, the relative contribution of ASIC currents to total synaptic current is less than 9 % (8.29 ± 2.24). Our experiments using 5b and suramin suggest an even lower percentage. Indeed, the residual currents were nearly unaffected in presence of 5b (1 ¼M) but strongly suppressed (to 16.9 ± 4.3 % converse off white of control) by suramin at 200 ¼M concentration.

Since the density of proton-activated currents (evoked by pH shift to 5) is ~ 75 pA/pF in amygdala and 20 pA/pF in hippocampus [ 8 ], a much reduced proton-mediated component of synaptic current in the hippocampus may be expected. In our experiments, however, the absolute value of inward synaptic current suppressed by ASIC antagonists is about 40 60 pA. As for the current mediated by ASICs in hippocampal GABAergic synapses, we believe this was undetectable due to its small absolute and relative amplitude.Functional interaction between ASICs and GABA A -receptors in isolated neurons has been recently demonstrated [ 10 , 11 ].

Indeed, this should be expected if the effect of 5b on inward PSCS in the absence of bicuculline is due to crosstalk between ASICs and GABA A -receptors, because the crosstalk in isolated neurons was blocked by antagonists of GABA A -receptors- receptors bicuculline and picrotoxin [ 10 ].Within the framework of this assumption, differential effects of the ASICs antagonists on inward and outward PSCs which we off white converse observed in our experiments would indicate that this interaction is voltage-dependent. In this regard, possibility to alter GABA-currents decay by changing voltage [ 37 , 38 ] and activation of ASICs [ 11 ] may be not just a coincidence.

Considering our results and previously published data, we conclude that the effect of the ASIC blockers on GABAegic synaptic transmission is due to an at least partially postsynaptic but (predominantly) modulatory mechanism. Our results may be of importance for applied pharmacology, because ASICs are considered as therapeutic targets for neurological diseases and ASIC blockers as potential neuroprotectors [ 40 ].