Changes in extracellular K+ evoked by GABA, THIP and baclofen in the guinea-pig hippocampal slice

Abstract

Changes in [K+]0 evoked by the inhibitory amino acid transmitter, GABA (gamma-aminobutyric acid) and its agonists were recorded with ion-selective microelectrodes in the CA1 stratum pyramidale of guinea-pig hippocampal slices. Bath applications of GABA (0.1-10 mM) produced dose-dependent increases in [K+]0 (EC50 = 4 mM, Rmax = 1.6 mM), with a peak and decline during exposure, followed by undershoot during recovery. In contrast the selective GABAA agonist, THIP (4,5,6,7-tetrahydroisoxazolo-(5,4-c)-pyridin-3-ol) (0.01-1 mM) showed approximately ten-fold greater potency and evoked only increases in [K+]0 (EC50 = 0.5 mM, Rmax = 2 mM). Reduction of temperature from 34 degrees to 22 degrees C caused a more than two-fold augmentation of the K+0 accumulation evoked by GABA, but no change in that due to THIP. The GABAA antagonist, BMI (bicuculline methiodide) (100 microM) completely blocked responses to THIP and partially antagonized those to GABA. Responses to GABA were synergistically enhanced by pentobarbital (100 microM). Only small, delayed and inconsistent changes could be evoked by relatively high concentrations of the GABAB agonist, DL-baclofen (0.01-1 mM). The K+ changes evoked by GABA appear to be mediated by the activation of GABAA receptors with low affinity and to be related to their depolarizing action. Although the response includes an electrogenic component which suggests the involvement of Na-dependent transmitter uptake/transport, the increase in K+0 probably reflects an outward counter/co-transport of K+ with Cl/HCO3 anion shifts and/or activation of a voltage-dependent K+ conductance.

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

“…10B, both the slow interictal events and the associated increases in [K + ] o recorded during blockade of excitatory glutamatergic receptors are abolished by pharmacological activation of μ-opioid receptors; as already mentioned, this procedure blocks the release of GABA from interneurons. Second, increases in [K + ] o can be induced by application of exogenous GABA or GABA A (but not GABA B ) receptor agonists in the presence of tetrodotoxin, thus ruling out a meaningful contribution of action potential firing (Barolet and Morris, 1991); it should be emphasized that in this pioneering study, Barolet and Morris (1991) (Smirnov et al, 1999;Kaila et al, 1997). This experimental procedure induces an intracellular response that is almost identical to what seen during the slow interictal spikes induced by 4AP (Fig.…”

“…Recently, Viitanen et al (2010) have proposed that the elevation in [K + ] o induced by high-frequency stimulation or GABA A receptor agonist application are generated by the KCC2 and that the transportermediated KCl extrusion is critically dependent on the bicarbonate-driven accumulation of [Cl − ] i . The [K + ] o increases could also be contributed by the firing of action potentials generated by interneurons discharging during the synchronous GABA receptor-mediated potential (Benardo, 1997), although the data obtained by Barolet and Morris (1991) during blockade of voltage-gated Na + channels suggest that this is not a significant mechanism.…”

“…Third, GABA A receptormediated depolarizations are contributed by HCO 3 − currents that have quite positive reversal potentials (−10 to −15 mV) (Staley et al, 1995;Lamsa and Kaila, 1997;Kaila et al, 1993Kaila et al, , 1997Rivera et al, 2005). Fourth, as discussed in Section 5.2.2, postsynaptic GABA A receptor activation can produce per se increases in extracellular K + concentration ([K + ] o ) (Barolet and Morris, 1991), a phenomenon that is known to depolarize neighboring nerve cells and to cause seizure activity (Zuckermann and Glaser, 1968). Fifth, HCO 3 − dependent depolarization may lead to the activation of voltage-gated Ca 2+ channels (Autere et al, 1999).…”

Activation of specific neuronal networks leads to different seizure onset types

“…40 Finally, activation of both PV and SOM interneurons leads to the release of GABA, which has been shown to result in an increase in extracellular [K + ] regardless of target compartments. 41 …”

GABAergic networks jump‐start focal seizures

“…3B) 31 that are known to accompany synchronous neuronal activity. [39][40][41][42] However, and even more important in the context of our hypothesis stating that seizure onset rests on "excessive GABAergic signaling," increases in extracellular potassium are induced by activation of GABA A receptors following application of GABA 39 or sustained interneuron activity, such as that occurring at seizure onset in rodent brain slices and in slices of human dysplastic cortex maintained in vitro. 23,25,[43][44][45][46] An explanation for these GABA A receptor-dependent elevations in extracellular potassium rests on the intracellular chloride accumulation that is known to occur in neurons once postsynaptic GABA A receptors are activated; this process increases the activity of the potassium-chloride cotransporter (KCC2), thus causing the efflux in the extracellular space of both potassium and chloride ions.…”