GABA_B receptors in neocortical and hippocampal pyramidal neurons are coupled to different potassium channels

Abstract

Classically, GABA receptors are thought to regulate neuronal excitability via G-protein-coupled inwardly rectifying potassium (GIRK) channels. Recent data, however, indicate that GABA receptors can also activate two-pore domain potassium channels. Here, we investigate which potassium channels are coupled to GABA receptors in rat neocortical layer 5 and hippocampal CA1 pyramidal neurons. Bath application of the non-specific GIRK channel blocker barium (200 μm) abolished outward currents evoked by GABA receptors in CA1 pyramidal, but only partially blocked GABA responses in layer 5 neurons. Layer 5 and CA1 pyramidal neurons also showed differential sensitivity to tertiapin-Q, a specific GIRK channel blocker. Tertiapin-Q partially blocked GABA responses in CA1 pyramidal neurons, but was ineffective in blocking GABA responses in neocortical layer 5 neurons. Consistent with the idea that GABA receptors are coupled to two-pore domain potassium channels, the non-specific blockers quinidine and bupivacaine partially blocked GABA responses in both layer 5 and CA1 neurons. Finally, we show that lowering external pH, as occurs in hypoxia, blocks the component of GABA responses mediated by two-pore domain potassium channels in neocortical layer 5 pyramidal neurons, while at the same time revealing a GIRK channel component. These data indicate that GABA receptors in neocortical layer 5 and hippocampal CA1 pyramidal neurons are coupled to different channels, with this coupling pH dependent on neocortical layer 5 pyramidal neurons. This pH dependency may act to maintain constant levels of GABA inhibition during hypoxia by enhancing GIRK channel function following a reduction in two-pore domain potassium channel activity.

Dendritic GABAB receptors control nonlinear information transfer along the dendro-somatic axis in layer 5 pyramidal neurons

“…Tertiapin reduced the baclofen-induced hyperpolarization by 54.1 ± 7.6% in the dendrite, consistent with a functionally significant contribution of GIRK channels to the baclofen-induced hyperpolarization (Extended Data Fig.4A). The incomplete block of the baclofen-induced hyperpolarization by tertiapin is in agreement with recent reports suggesting that other K + channels such as two-pore domain K + channels also contribute to GABAB-mediated membrane potential hyperpolarizations in L5 pyramidal neurons and entorhinal stellate cells (Deng et al, 2009;Breton & Stuart, 2017). Importantly, tertiapin partially blocked the effect of baclofen on the voltage-dependence of input and transfer resistances ( Fig.4F-J), suggesting that GIRK channel activation in the dendrite was an important factor that mediated the effect of dendritic GABABR activation.…”

“…The main reason for the powerful impact of the seemingly small hyperpolarization by GABABR-activated K + channels (Newberry & Nicoll, 1984;Palmer et al, 2012;Breton & Stuart, 2017) was due to its impact on other voltage-dependent conductances in the dendrites. While the local somatic and dendritic input resistances were weakly voltage dependent, the transfer resistance from dendrite to soma (Kds) strongly depended on the dendritic membrane potential doubling at an estimated rate of every 28.7 mV depolarization step ( Fig.3D).…”

“…GABABR activation is well known to increase conductance through GIRK channels (Newberry & Nicoll, 1984;Palmer et al, 2012) and has been reported to recruit additionally other K + channels such as two-pore domain K + channels in L5 pyramidal neurons and entorhinal stellate cells (Deng et al, 2009;Breton & Stuart, 2017). To test whether an increase of the K + -mediated membrane conductance in the dendritic compartment was sufficient to cause the experimentally observed changes in dendritic input resistance and transfer resistance after the baclofen puff, we fitted the twocompartmental model to the membrane potential responses in the control condition for all experiments in Fig.…”

Acetylcholine release inhibits distinct excitatory inputs onto hippocampal CA1 pyramidal neurons via different cellular and network mechanisms

“…5B, p = 0.0758; t = 1.899; df = 16; n = 17 cells from 6 animals). To further test the involvement of the GIRK channels, we attempted to directly inhibit the GIRK conductance via extracellular application of Ba 2+ (200 M) (Breton and Stuart 2017). As shown in Figure 5C, extracellular application of Ba 2+ blocked the ACh-mediated reduction of PPR ( Fig.…”

Respiratory rhythm generation and pattern formation: oscillators and network mechanisms

“…Slow neuromodulatory inhibition comprises those mechanisms activated through intracellular signal transduction pathways by receptor-ligand binding and mediating the opening or closing or modifying the molecular biophysical properties of membrane ion channels. The activated currents transmit net outward potassium conductances (Breton and Stuart, 2017;Pfeiffer and Zhang, 2007;Wagner and Dekin, 1993) and the inhibited currents transmit net inward calcium conductances in electroconductive neurolemmal membranes (Cai et al, 2018;Gahwiler and Brown, 1985;Li et al, 1995;Misgeld et al, 1995;Mizuta et al, 2008;Newberry and Nicoll, 1985;Nicoll et al, 1990;Thalmann, 1988;Zhang et al, 1999).…”