The role of bicarbonate in GABAA receptor‐mediated IPSPs of rat neocortical neurones.

Abstract

SUMMARY1. The ionic mechanism underlying the fast, GABAA receptor-mediated inhibitory postsynaptic potential (IPSPA) was examined in rat neocortical neurones using intracellular recording techniques. Synaptic responses were evoked by orthodromic stimulation applied to the subcortical white matter or to the pial surface. All experiments were carried out at a constant extracellular Cl-concentration.2. The resting membrane potential was -76-2 + 1I0 mV (mean+s. E. M., n = 32) and in most cells IPSPA was depolarizing. The reversal potential of IPSPA (EIPSP-A) was -70-2 + 0 9 mV (n = 32) and that of a more slowly developing hyperpolarizing response (IPSPB) was -91 4 + 1 3 mV (n = 28).3. An examination of the temporal relationships between excitatory postsynaptic potentials (EPSPs) and IPSPAS in different cells suggested that, despite partial overlap of these responses, EPSPs had little influence on the measured values of DEIPSP-A, 4. Application of 20 mm trimethylamine (TriMA), a membrane-permeant weak base which is expected to produce a rise in pHi (and hence in intracellular HC03-), induced a reversible positive shift in EIPSP-A of up to + 9-0 mV (mean + 4-2 mV) at an extracellular pH (pH.) of 7 4. In some experiments, the shift in reversal potential was associated with a change in the polarity of IPSPA from hyperpolarizing to depolarizing.5. Application of 20 mm lactate (a membrane-permeant weak acid which is expected to produce a fall in pHi and hence in intracellular HCO3 ) at pH. 7 0 produced a hyperpolarizing shift in EIPSP-A of up to -75 mV (mean -56 mV). In some experiments, exposure to lactate changed the polarity of IPSPA from depolarizing to hyperpolarizing.6. Changes in pH. from 7-4 to 7-0 reduced the effect of TriMA and augmented that of lactate on EIPSP-A' as could be expected on the basis of the pHo-dependent change in the fraction of membrane permeable non-charged weak base or acid.

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

“…As discussed in Section 9, this mechanism may play an important role in neonatal seizures (Dzhala et al, 2005(Dzhala et al, , 2010Nardou et al, 2009). 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).…”

Mice with targeted Slc4a10 gene disruption have small brain ventricles and show reduced neuronal excitability

“…For instance, GABA A receptor channels mediate a significant net efflux of HCO 3 Ϫ under physiological conditions (32,33), and an increase in pH i induces an increase in the depolarizing bicarbonate current component in ionotropic GABAergic responses (34). Furthermore, the depolarizing action of HCO 3 Ϫ efflux by GABA A receptors drives a conductive net uptake of chloride, resulting in chloride-mediated positive shifts in GABA A receptor responses (35).…”

GABAergic Depolarization of the Axon Initial Segment in Cortical Principal Neurons Is Caused by the Na–K–2Cl Cotransporter NKCC1

“…Loss of space clamp is expected to be even smaller in the proximal parts of the dendrites (also recorded at a 50 m distance from the soma) than at the AIS. In the present context, it is notable that, in the whole-cell clamp experiments in which the calculated somatic E GABA is Ϫ68 mV (corrected for intracellular bicarbonate; E Cl of Ϫ77 mV) (Kaila et al, 1993;Kaila, 1994;Farrant and Kaila, 2007), the DGCs were obviously able to cope with part of this minor imposed load (7 mM Cl Ϫ ) even in the somatic compartment, and, hence, the measured somatic E GABA is more negative (Ϫ74.2 mV, corresponding to 4.9 mM intracellular Cl Ϫ ). A similar deviation of the measured intracellular Cl Ϫ from the calculated passive distribution was observed in the neocortical layer 2/3 pyramidal neurons.…”

“…However, the mere absence of KCC2 cannot account for the strikingly positive E GABA values at the AIS, because in the complete absence of Cl Ϫ transport, E GABA would achieve a level close to and only slightly more depolarized than the resting membrane potential (Kaila et al, 1993;Farrant and Kaila, 2007). Thus, the depolarizing GABA A receptor-mediated response at the AIS requires the presence of a Cl Ϫ uptake mechanism.…”