Abstract
Rapid acidification occurring during synaptic vesicle release can activate acid-sensing ion channels (ASICs) both on pre- and postsynaptic neurons. In the latter case, a fraction of postsynaptic current would be mediated by cation-selective acid-sensing ion channels. Additionally, in both cases, activation of acid-sensing ion channels could modulate synaptic strength by affecting transmitter release and/or sensitivity of postsynaptic receptors. To address potential involvement of acid-sensing ion channels in mediation/modulation of synaptic transmission at hippocampal GABAergic synapses, we studied effects of three structurally different blockers of acid-sensing ion channels on evoked postsynaptic currents using the patch-clamp technique. We found that GABAergic postsynaptic currents, recorded below their reversal potential as inward currents, are suppressed by all the employed blockers of acid-sensing ion channels. These currents were suppressed by ~ 20 % in the presence of a novel blocker 5b (1 μM) and by ~30 % in the presence of either amiloride (25 μM) or diminazene (20 μM). In the same cells the suppression of postsynaptic currents, recorded above their reversal potential as outward currents was statistically insignificant. These results imply that the effects of blockers in our experiments are at least partially postsynaptic. On the other hand, in the case of mediation of a fraction of postsynaptic current by acid-sensing ion channels, an increase of outward currents would be expected under our experimental conditions. Our analysis of a bicuculline-resistant fraction of postsynaptic currents also suggests that effects of the blockers are predominantly modulatory. In this work we present evidence for the first time that acid-sensing ion channels play a functional role at hippocampal GABAergic synapses. The suppressing effect of the blockers of acid-sensing ion channels on GABAergic transmission is due, at least partially, to a postsynaptic but (predominantly) modulatory mechanism. We hypothesize that the modulatory effect is due to functional crosstalk between ASICs and GABAA-receptors recently reported in isolated neurons, however, verification of this hypothesis is necessary.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0269-4) contains supplementary material, which is available to authorized users.
Highlights
acid-sensing ion channels (ASICs) are abundant in many brain areas and are known to have important physiological functions
The effect of compound 5b on GABAergic Postsynaptic currents (PSCs) is likely to be due to predominantly modulatory action related to rapid synaptic acidification Effect of compound 5b on GABAergic PSCs in hydroxyethyl]piperazine-N’-[2-ethanesulfonic acid] (HEPES) 2 solution If a fraction of postsynaptic current at hippocampal GABAergic synapses is mediated by cation-selective ASICs, ionic composition of PSCs will be comprised by both cations and Cl- anions
The effect of compound 5b on GABAergic PSCs is attenuated in HEPES 10 solution To check whether the effect of 5b is related to endogenously occurring acidification, in a separate series of experiments we studied the effect of this compound in extracellular solution with enhanced concentration of proton buffer (HEPES)
Summary
ASICs are abundant in many brain areas and are known to have important physiological functions. Because of rapid desensitization of ASIC-mediated currents, synapses are among the few places where they can be activated under physiological conditions and, mediate their physiological role. While under physiological conditions the brain’s extracellular pH is reasonably constant, neural activity can induce transient and localized pH fluctuations, in particular, due to release of synaptic vesicles which have a pH of ~5.2–5.7. Storozhuk et al Molecular Brain (2016) 9:90 possible involvement of ASICs in the regulation of GABAergic transmission is still poorly investigated. We have started to address this question by examining possible effects of several ASIC blockers on evoked GABAergic PSCs in hippocampal cell culture. It should be noted that ASICs are in any case naturally present in hippocampal neurons as detail studied in [8, 12,13,14,15,16]
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