Thus, while the effect of 5b on the converse look inward currents could be explained by the direct involvement of ASICs in PSC generation as observed in the amygdala [ 5 ], the lack of an increase of the outward currents suggests that the effect of 5b is predominantly modulatory. Lack of apparent shift of estimated PSCs reversal potential (-0.75 ± 0.26 mV, n = 8) after application of 5b also supports this suggestion. (see Methods for details of estimating PSCs reversal potential). Nevertheless, to further verify this point we tried to pharmacologically isolate/enhance a fraction of synaptic current that is not mediated by GABA A -receptors (residual current) and study some of its properties.

In spite of growing evidence indicating that the density of ASICs is substantially higher in GABAergic interneurons than in glutamatergic cells [ 17 ] and recent demonstration of functional crosstalk converse all star between ASICs and GABA A -receptors [ 10 , 11 ], the possible involvement of ASICs in the regulation of GABAergic transmission remained unclear. In our work we present evidence for the first time that ASICs play a functional role at hippocampal GABAergic synapses. This role is mediated, converse all stars at least partially, by a postsynaptic but (predominantly) modulatory mechanism.We found that GABAergic postsynaptic currents, recorded below their reversal potential as inward currents, are suppressed by all the employed blockers of ASICs.

In the same cells the suppression of postsynaptic currents, recorded above their reversal potential as outward currents was statistically insignificant.Apart from the chemical dissimilarity of amiloride and diminazene, they are structurally different [ 24 ], and mechanisms of their action on ASICs are different as well [ 24 ]. Similarly, amiloride and 5b have different mechanisms of action on ASICs [ 21 ]. converse off white Indeed, 5b is an orthosteric antagonist of ASIC1 [ 21 ] while amiloride is an open channel blocker [ 33 ].

On the other hand, direct involvement of ASICs in PSCs generation documented for lateral amygdala neurons [ 5 ], does not seemingly occur in hippocampal neurons [ 6 , 36 ]. Our results tend to agree with the latter observations. Indeed, under our experimental conditions, if a substantial fraction of synaptic current is mediated by ASICs, a decrease in the net inward current, and an increase in the net outward current would be expected once ASICs are blocked. While in the presence of ASIC antagonists we did observe a decrease of the inward currents and a small decrease in the outward currents.

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 off white converse 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 ].

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 ].