Somatic and dendritic GABA_B receptors regulate neuronal excitability via different mechanisms

Abstract

Breton J-D, Stuart GJ. Somatic and dendritic GABA B receptors regulate neuronal excitability via different mechanisms. J Neurophysiol 108: 2810 -2818, 2012. First published September 5, 2012 doi:10.1152/jn.00524.2012.-GABA B receptors play a key role in regulating neuronal excitability in the brain. Whereas the impact of somatic GABA B receptors on neuronal excitability has been studied in some detail, much less is known about the role of dendritic GABA B receptors. Here, we investigate the impact of GABA B receptor activation on the somato-dendritic excitability of layer 5 pyramidal neurons in the rat barrel cortex. Activation of GABA B receptors led to hyperpolarization and a decrease in membrane resistance that was greatest at somatic and proximal dendritic locations. These effects were occluded by low concentrations of barium (100 M), suggesting that they are mediated by potassium channels. In contrast, activation of dendritic GABA B receptors decreased the width of backpropagating action potential (APs) and abolished dendritic calcium electrogenesis, indicating that dendritic GABA B receptors regulate excitability, primarily via inhibition of voltage-dependent calcium channels. These distinct actions of somatic and dendritic GABA B receptors regulated neuronal output in different ways. Activation of somatic GABA B receptors led to a reduction in neuronal output, primarily by increasing the AP rheobase, whereas activation of dendritic GABA B receptors blocked burst firing, decreasing AP output in the absence of a significant change in somatic membrane properties. Taken together, our results show that GABA B receptors regulate somatic and dendritic excitability of cortical pyramidal neurons via different cellular mechanisms. Somatic GABA B receptors activate potassium channels, leading primarily to a subtractive or shunting form of inhibition, whereas dendritic GABA B receptors inhibit dendritic calcium electrogenesis, leading to a reduction in bursting firing.

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

“…To investigate the possibility that somatic and dendritic GABA B receptors have different sensitivity to tertiapin‐Q, we also tested the impact of tertiapin‐Q on dendritic GABA B responses in layer 5 pyramidal neurons during bath applications of baclofen (20 μ m ). These experiments showed that dendritic input resistance ( R n ) measured between 300 and 500 μm from the soma ( n = 5; average: 436 ± 13 μm) decreased significantly from 26.4 ± 1.5 MΩ in control to 19.8 ± 1.5 MΩ in the presence of baclofen ( n = 5; P < 0.05), as previously described (Breton & Stuart, ). Concomitant application of tertiapin‐Q (100 n m ) with baclofen failed to block the impact of baclofen on dendritic input resistance ( R n baclofen + tertiapin‐Q: 19.4 ± 1.9 MΩ; n = 5, P > 0.05).…”

“…Previous studies indicate that presynaptic GABA B receptors downregulate voltage-activated calcium channels, restricting neurotransmitter release from synaptic terminals (Scholz & Miller, 1991;Campbell et al, 1993;Mintz & Bean, 1993). Postsynaptic GABA B receptors can also modulate voltage-activated calcium channels in dendrites and spines (Kavalali et al, 1997;Sabatini & Svoboda, 2000;Chalifoux & Carter, 2011), where they regulate dendritic excitability and neuronal output both in vitro and in vivo (Perez-Garci et al, 2006;Breton & Stuart, 2012;Palmer et al, 2012). GABA B receptors also regulate neuronal excitability via the activation of potassium channels leading to a slow membrane hyperpolarization, first identified in hippocampal neurons (Gahwiler & Brown, 1985;Newberry & Nicoll, 1985;Luscher et al, 1997;Chen & Johnston, 2005).…”

Precision of Inhibition: Dendritic Inhibition by Individual GABAergic Synapses on Hippocampal Pyramidal Cells Is Confined in Space and Time

“…Addressing inhibition of Ca 2+ processes more directly, a number of elegant studies have described dendritic inhibition of Ca 2+ -dependent spikes upon activation of single (Larkum et al, 1999) or multiple (Miles et al, 1996;Tsubokawa and Ross, 1996) dendrite-targeting inhibitory interneurons in brain slices, as well as in vivo (Murayama et al, 2009). On top of GABA A -dependent effects, some of this inhibition is also mediated by GABA B receptor activation (Pé rez-Garci et al, 2006Chalifoux and Carter, 2011;Breton and Stuart, 2012). On a population level, dendritic inhibition acts as a key regulator of neuronal input-output transformations (Lovett-Barron et al, 2012;Mü ller et al, 2012).…”

Single/Dual Alkaline Earth Metal‐Doped Hollow Nanoparticles as Nanocarrier for Accelerating Neurite Development by Activating pERK and pJNK

“…Although the specific mechanism by which the pAkt pathway affects neuronal differentiation in AEM ion‐treated PC12 cells is ambiguous, some studies have suggested that Akt could be phosphorylated to pAkt through Ca‐ion channel stimulation . In the case of the Ba 2+ ion, its ability to pass through a potassium‐ion channel and a Ca‐ion channel may result in very high pAkt expression . Two other signaling pathways, pERK and pp38, are known to affect the neurite outgrowth of PC12 cells.…”