GABAB receptor‐mediated inhibition of Ca2+ currents and synaptic transmission in cultured rat hippocampal neurones.

Scholz, Kenneth P.; Miller, Richard J.

doi:10.1113/jphysiol.1991.sp018900

Cited by 172 publications

(114 citation statements)

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“…There is a large amount of evidence that baclofen reduces voltagesensitive Ca2+ currents in dorsal root ganglion neurones (Dunlap & Fischbach, 1981;Dolphin & Scott, 1987) and cultured hippocampal cells (Scholz & Miller, 1991). Presynaptic reductions by baclofen of synaptic transmission have been observed in other neuronal preparations (Davies, 1981;Lanthorn & Cotman, 1981;Peet & McLennan, 1986;Deisz & Prince, 1989;Harrison, 1990;Scholz & Miller, 1991), although Misgeld, MUller & Brunner (1989) The functional results of baclofen application in vivo are likely to be complex and to vary with the degree of receptor activation and the level and quality of ongoing synaptic input. The greater sensitivity ofIPSPs compared to EPSPs could, under certain circumstances, result in an overall excitatory effect if a tonic inhibition were present.…”

Section: Discussionmentioning

confidence: 99%

“…This hyperpolarizing action is mediated by G protein activation and is pertussis toxin sensitive (Andrade, Malenka & Nicoll, 1986;Thalmann, 1988;Colmers & Pittman, 1989). GABAB receptor activation can also cause presynaptic inhibition of both excitatory (Lanthorn & Nadler, 1982;Blaxter & Carlen, 1985;Dutar & Nicoll, 1988;Scholz & Miller, 1991) and inhibitory synaptic events (Peet & McLennan, 1986;Howe, Sutor & Zieglginsberger, 1987;Deisz & Prince, 1989;Harrison, 1990;Scholz & Miller, 1991). The pre-and postsynaptic effects may not be mediated by the same mechanisms as the former appear to be resistant to pertussis toxin pretreatment (Dutar & Nicol, 1988;Colmers & Williams, 1988;Colmers & Pittman, 1989;Harrison, 1990; but see Scholz & Miller, 1991).…”

Section: Introductionmentioning

confidence: 99%

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The actions of baclofen on neurones and synaptic transmission in the nucleus tractus solitarii of the rat in vitro.

Brooks

Glaum

Miller

et al. 1992

The Journal of Physiology

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113

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SUMMARY1. Intracellular and whole-cell patch recordings were made from sixty-seven neurones located in the nucleus tractus solitarii (NTS) in transverse slices of rat brainstem.2. Baclofen at concentrations of 2-20 ftM caused hyperpolarization from normal resting membrane potentials (Vm). This response was associated with a decrease in input resistance (Rm) tested by current pulses in discontinuous current clamp mode when membrane potential was restored to control level by current injection. In single electrode discontinuous voltage clamp mode, baclofen'at these concentrations caused a small (< 50 pA) outward current associated with increased membrane conductance measured by voltage steps from holding potentials (Vh) of -50 or -60 mV. Current-voltage relations at these Vhs and the results of varying Vh between -50 and -110 mV during responses to baclofen gave a reversal potential of -73 mV. The amplitudes of baclofen responses were related to K+ concentration tested by comparing responses in media containing 1-24 mm extracellular K', indicating that postsynaptically baclofen acts via a K+ conductance.3. These effects were still apparent in the presence of tetrodotoxin (which did not abolish all spontaneous synaptic activity) and also in medium containing a combination of C02+, the excitatory amino acid antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and the GABAA antagonist bicuculline which blocked synaptic activity.4. The amplitude and frequency of spontaneous postsynaptic potentials (spPSPs) and spontaneous postsynaptic currents (spPSCs) were reduced by baclofen at concentrations (1 /LM or less) which had no effect on membrane potential or holding current in current or voltage clamp recordings respectively.5. The amplitude of evoked excitatory (evEPSPs/evEPSCs) and inhibitory (evIPSPs/evIPSCs) synaptic events elicited by electrical stimulation in the vicinity of the tractus solitarius (TS) was reduced by low concentrations of baclofen (250 nM-1 jM) which did not produce discernible postsynaptic responses.6. In order to examine the effects of baclofen on excitatory synaptic events MS 9797 P. A. BROOKS AND OTHERS without contamination with inhibitory events, stimulation of the TS was carried out in the presence of bicuculline. Conversely to investigate actions on purely inhibitory synaptic responses experiments were carried out with CNQX in the bathing solution. Inhibitory synaptic responses could still be evoked, presumably by stimulation of interneurones in the vicinity of the TS. IPSPs/IPSCs were more sensitive to baclofen than EPSPs/EPSCs.7. The effects of baclofen on membrane potential or holding current and PSP/PSCs were antagonized by 2-hydroxysaclofen (400 /M) confirming that baclofen was acting at y-aminobutyric acid (GABA)B receptors.8. The pre-and postsynaptic depressant effects of baclofen are discussed in relation to the physiological effects of baclofen application in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The actions of baclofen on neurones and synaptic transmission in the nucleus tractus solitarii of the rat in vitro.

Brooks

Glaum

Miller

et al. 1992

The Journal of Physiology

Self Cite

113

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“…Cultured hippocampal neurons are amenable to adenoviral infection yet retain many of the features of more intact preparations, including robust, PTX-sensitive presynaptic inhibition mediated by adenosine A 1 receptors and GABA B receptors (33,34). In uninfected control neurons, application of adenosine (20 M) or baclofen (50 M) produced a marked inhibition of excitatory postsynaptic currents (EPSCs; 84 Ϯ 2% and 81 Ϯ 3% inhibition, respectively, n ϭ 13; Fig.…”

Section: Subunitsmentioning

confidence: 99%

“…, Ͼ24 h) abolished adenosine-and baclofen-induced presynaptic inhibition, as reported (33,34), in uninfected control neurons (data not shown; n ϭ 18), and in pAdEasy1-GFP ϩ ␤-gal-infected neurons (adenosine: 0 Ϯ 3%; baclofen: 0 Ϯ 1%; n ϭ7; Fig. 1 A).…”

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confidence: 98%

Endogenous regulators of G protein signaling proteins regulate presynaptic inhibition at rat hippocampal synapses

Chen

Lambert

2000

Proc. Natl. Acad. Sci. U.S.A.

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Presynaptic inhibition mediated by G protein-coupled receptors (GPCRs) can develop and decay in a few seconds. This time course is too rapid to be accounted for by the intrinsic GTPase activity of G␣ subunits alone. Here, we test the hypothesis that endogenous regulators of G protein signaling (RGS proteins) are required for rapid, brief presynaptic inhibition. Endogenous G protein ␣ subunits were uncoupled from GPCRs by treating cultures with pertussis toxin (PTX). Adenoviral expression of mutant PTX-insensitive (PTX-i) G␣i1-3 or G␣o subunits rescued adenosine-induced presynaptic inhibition in cultured hippocampal neurons. Expression of double mutant G␣ i1 or G␣o subunits that were both PTX-insensitive and unable to bind RGS proteins (PTX͞RGS-i) also rescued presynaptic inhibition. Presynaptic inhibition mediated by PTX͞RGS-i subunits decayed much more slowly after agonist removal than that mediated by PTX-i subunits or native G proteins. The onset of presynaptic inhibition mediated by PTX͞RGS-i G␣o was also slower than that mediated by PTX-i G␣ o. In contrast, the onset of presynaptic inhibition mediated by PTX͞RGS-i G␣i1 was similar to that mediated by PTX-i G␣ i1. These results suggest that endogenous RGS proteins regulate the time course of G protein signaling in mammalian central nervous system presynaptic terminals. The release of neurotransmitter from most presynaptic terminals is regulated by activation of G protein-coupled receptors (GPCRs) (1, 2). These receptors may be autoreceptors for ligands released at the same synapse, or heteroreceptors for a wide variety of small molecules [e.g., ␥-aminobutyric acid (GABA), glutamate, or adenosine] or peptides. The most common type of regulation is presynaptic inhibition mediated by heterotrimeric G proteins composed of pertussis toxin (PTX)-sensitive ␣ subunits (G␣ i and͞or G␣ o ) and ␤␥ dimers. Receptor activation promotes nucleotide exchange, which is followed by dissociation of ␣-GTP and ␤␥. Free ␤␥ dimers directly alter the gating of the calcium channels that mediate neurotransmitter release in a manner that makes these channels reluctant to open (3). The resulting inhibition of presynaptic calcium influx can largely account for presynaptic inhibition mediated by GPCRs (4, 5), although mechanisms downstream from calcium influx also may be important in some cases (5). Presynaptic inhibition is terminated by heterotrimer reassociation after hydrolysis of ␣-GTP to ␣-GDP (6).Presynaptic inhibition decays in a few seconds after agonist removal (7,8). This agrees well with the time course of inhibition of somatic calcium channels (7, 9-11) and inhibition of presynaptic calcium influx (8). Activity-dependent release of endogenous agonists produces presynaptic inhibition with a similarly rapid time course (8,(12)(13)(14). The decay of presynaptic inhibition is far too rapid to be accounted for by the intrinsic GTPase activity of PTX-sensitive ␣ subunits alone (15). In other systems regulators of G protein signaling (RGS proteins) act as GTPaseaccelerating protein...

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“…In addition, GABA B receptors can act presynaptically to inhibit voltage-dependent calcium channels and thereby modulate transmitter release. Whereas this action of GABA B receptors was initially thought only to be important in presynaptic terminals (Campbell et al 1993;Mintz and Bean 1993;Scholz and Miller 1991), there is increasing evidence that GABA B receptors can also act to modulate voltage-dependent calcium channels in dendrites and spines (Chalifoux and Carter 2011;Kavalali et al 1997;Sabatini and Svoboda 2000), where they can influence dendritic excitability (Perez-Garci et al 2006) as well as modulate N-methyl-D-aspartate (NMDA) receptor activation (Chalifoux and Carter 2010).…”

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confidence: 99%

Somatic and dendritic GABA_B receptors regulate neuronal excitability via different mechanisms

Breton

Stuart

2012

Journal of Neurophysiology

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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.

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GABAB receptor‐mediated inhibition of Ca2+ currents and synaptic transmission in cultured rat hippocampal neurones.

Cited by 172 publications

References 50 publications

The actions of baclofen on neurones and synaptic transmission in the nucleus tractus solitarii of the rat in vitro.

The actions of baclofen on neurones and synaptic transmission in the nucleus tractus solitarii of the rat in vitro.

Endogenous regulators of G protein signaling proteins regulate presynaptic inhibition at rat hippocampal synapses

Somatic and dendritic GABA_B receptors regulate neuronal excitability via different mechanisms

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GABAB receptor‐mediated inhibition of Ca2+ currents and synaptic transmission in cultured rat hippocampal neurones.

Cited by 172 publications

References 50 publications

The actions of baclofen on neurones and synaptic transmission in the nucleus tractus solitarii of the rat in vitro.

The actions of baclofen on neurones and synaptic transmission in the nucleus tractus solitarii of the rat in vitro.

Endogenous regulators of G protein signaling proteins regulate presynaptic inhibition at rat hippocampal synapses

Somatic and dendritic GABAB receptors regulate neuronal excitability via different mechanisms

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Somatic and dendritic GABA_B receptors regulate neuronal excitability via different mechanisms