Incremental conductance levels of GABA<sub>A</sub> receptors in dopaminergic neurones of the rat substantia nigra pars compacta

Guyon, Alice; Laurent, Stanislas; Paupardin‐Tritsch, Danièle; Rossier, Jean; Eugène, Daniel

doi:10.1111/j.1469-7793.1999.0719u.x

Cited by 38 publications

(33 citation statements)

References 49 publications

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“…One study reported the detection of GABA A ␣1 subunit protein in dopamine neurons in humans (Petri et al, 2002), whereas two studies using single-cell RT-PCR in rodents failed to confirm this finding (Guyon et al, 1999;Okada et al, 2004), suggesting a minimal, if any, expression of ␣1 subunit in these cells. We investigated GABA neurotransmission in dopamine neurons using patch-clamp electrophysiology in acute slices.…”

Section: Duration Of Inhibition: a Driving Force For Neuronal Plasticitymentioning

confidence: 95%

Transcriptional Signatures of Cellular Plasticity in Mice Lacking the α1 Subunit of GABA_AReceptors

et al. 2006

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GABA A receptors mediate the majority of inhibitory neurotransmission in the CNS. Genetic deletion of the ␣1 subunit of GABA A receptors results in a loss of ␣1-mediated fast inhibitory currents and a marked reduction in density of GABA A receptors. A grossly normal phenotype of ␣1-deficient mice suggests the presence of neuronal adaptation to these drastic changes at the GABA synapse. We used cDNA microarrays to identify transcriptional fingerprints of cellular plasticity in response to altered GABAergic inhibition in the cerebral cortex and cerebellum of ␣1 mutants. In silico analysis of 982 mutation-regulated transcripts highlighted genes and functional groups involved in regulation of neuronal excitability and synaptic transmission, suggesting an adaptive response of the brain to an altered inhibitory tone. Public gene expression databases permitted identification of subsets of transcripts enriched in excitatory and inhibitory neurons as well as some glial cells, providing evidence for cellular plasticity in individual cell types. Additional analysis linked some transcriptional changes to cellular phenotypes observed in the knock-out mice and suggested several genes, such as the early growth response 1 (Egr1), small GTP binding protein Rac1 (Rac1), neurogranin (Nrgn), sodium channel ␤4 subunit (Scn4b), and potassium voltage-gated Kv4.2 channel (Kcnd2) as cell type-specific markers of neuronal plasticity. Furthermore, transcriptional activation of genes enriched in Bergman glia suggests an active role of these astrocytes in synaptic plasticity. Overall, our results suggest that the loss of ␣1-mediated fast inhibition produces diverse transcriptional responses that act to regulate neuronal excitability of individual neurons and stabilize neuronal networks, which may account for the lack of severe abnormalities in ␣1 null mutants.

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Section: Duration Of Inhibition: a Driving Force For Neuronal Plasticitymentioning

confidence: 95%

Transcriptional Signatures of Cellular Plasticity in Mice Lacking the α1 Subunit of GABA_AReceptors

et al. 2006

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“…Recent studies have shown that synaptic plasticity may enhance synaptically triggered burst firing and therefore underlie the acquisition of the burst response to a reward-predicting stimulus (Harnett et al 2009). Although changes in plasticity can be effected within minutes, changes in the balance between excitatory and inhibitory inputs are capable of modulating bursts quicker.…”

Section: Tipping the Scales: Generating Pauses And Burstsmentioning

confidence: 99%

“…Using a GABA A receptor time constant of 6 ms (;Brancucci et al 2004), a single channel conductance of 5-30 pS (⌬g; Guyon et al 1999;Macdonald and Olsen 1994), and a 50 Hz input rate (F), we calculate that 887-5,330 GABA A receptors must be activated by globus pallidus and substantia nigra pars reticulata inputs to achieve the 8 nS steady-state conductance (g ss ) used in the balanced configuration in Fig. 1D (g (Fujiyama et al 2002) times 2.5 GABA A receptors per gold particle (Nusser et al 1997)], this corresponds to a minimum ϳ1-8% of the total GABAergic synapses onto an SNc neuron (ϳ5,600 GABAergic synapses total; Henny et al 2009).…”

Section: High Conductance State Of the Dopaminergic Neuronmentioning

confidence: 99%

A Dynamic Role for GABA Receptors on the Firing Pattern of Midbrain Dopaminergic Neurons

Lobb

Wilson

Paladini

2010

Journal of Neurophysiology

120

112

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. Dopaminergic neurons are subject to a significant background GABAergic input in vivo. The presence of this GABAergic background might be expected to inhibit dopaminergic neuron firing. However, dopaminergic neurons are not all silent but instead fire in single-spiking and burst firing modes. Here we present evidence that phasic changes in the tonic activity of GABAergic afferents are a potential extrinsic mechanism that triggers bursts and pauses in dopaminergic neurons. We find that spontaneous singlespiking is more sensitive to activation of GABA receptors than phasic N-methyl-D-aspartate (NMDA)-mediated burst firing in rat slices (P15-P31). Because tonic activation of GABA A receptors has previously been shown to suppress burst firing in vivo, our results suggest that the activity patterns seen in vivo are the result of a balance between excitatory and inhibitory conductances that interact with the intrinsic pacemaking currents observed in slices. Using the dynamic clamp technique, we applied balanced, constant NMDA and GABA A receptor conductances into dopaminergic neurons in slices. Bursts could be produced by disinhibition (phasic removal of the GABA A receptor conductance), and these bursts had a higher frequency than bursts produced by the same NMDA receptor conductance alone. Phasic increases in the GABA A receptor conductance evoked pauses in firing. In contrast to NMDA receptor, application of constant AMPA and GABA A receptor conductances caused the cell to go into depolarization block. These results support a bidirectional mechanism by which GABAergic inputs, in balance with NMDA receptormediated excitatory inputs, control the firing pattern of dopaminergic neurons.

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“…Recombinant GABA A receptors are different from native GABA A receptors in that they never display single channel conductances greater than 40 pS, nor do drugs modulate their conductance, properties we and others have described for native nonsynaptic (extrasynaptic) GABA A receptors (3)(4)(5)(6)(7)(8). We have, however, been able to mimic the behavior exhibited by neuronal extrasynaptic GABA A receptors in a recombinant system and change the dispersion of receptors in the membrane simply by co-expressing the trafficking protein GABARAP with GABA A receptors (9).…”

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confidence: 99%

GABA Increases both the Conductance and Mean Open Time of Recombinant GABAA Channels Co-expressed with GABARAP

Luu

Gage

Tierney

2006

Journal of Biological Chemistry

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The single channel properties of recombinant ␥-aminobutyric acid type A (GABA A ) ␣␤␥ receptors co-expressed with the trafficking protein GABARAP were investigated using membrane patches in the outside-out patch clamp configuration from transiently transfected L929 cells. In control cells expressing ␣␤␥ receptors alone, GABA activated single channels whose main conductance was 30 picosiemens (pS) with a subconductance state of 20 pS, and increasing the GABA concentration did not alter their conductance. In contrast, when GABA A receptors were co-expressed with GABARAP, the GABA-activated single channels displayed multiple, high conductances (>40 pS), and GABA (>10 M) was able to increase their conductance, up to a maximum of 60 pS Inhibitory signals in human brains are mediated primarily by ␥-aminobutyric acid type A (GABA A ) 2 receptors. These ligandgated ion channels are composed of multimembrane-spanning subunits that assemble into pentamers and function by gating a pore selective for chloride ions. The targeting and organization of GABA A receptors at specific membrane locations are critical for their normal function. For example, GABA A receptors are clustered at inhibitory synapses but are also found both clustered and nonclustered at other sites on the neuronal cell surface (1, 2). These synaptic and nonsynaptic (extrasynaptic) sites reflect GABA A receptor involvement in both phasic and tonic signaling, respectively. The functional behavior of native GABA A receptors is complex. Much of the receptor's functional complexity has been attributed to its extensive structural heterogeneity as indicated by the 19 different genes identified to date (␣1-6, ␤1-3, ␥1-3, ␦, 1-3, ⑀, , and ).Recombinant GABA A receptors are different from native GABA A receptors in that they never display single channel conductances greater than 40 pS, nor do drugs modulate their conductance, properties we and others have described for native nonsynaptic (extrasynaptic) GABA A receptors (3-8). We have, however, been able to mimic the behavior exhibited by neuronal extrasynaptic GABA A receptors in a recombinant system and change the dispersion of receptors in the membrane simply by co-expressing the trafficking protein GABARAP with GABA A receptors (9). GABARAP (GABA A receptor-associated protein) was originally identified because of its physical association with GABA A receptors following their isolation by immunoprecipitation from solubilized rat brain (10). Subsequent immunolocalization data and the biochemical identification of the GABARAP interaction partners has led to the suggestion that it participates in trafficking and membrane fusion events underlying organizational processes at GABAergic synapses but does not remain associated with receptors once they are inserted at the synapse (11). In heterologous expression systems, recombinant GABARAP has been shown to promote clustering of ␥ subunit-containing GABA A receptors in the plasma membrane (9, 12). As a consequence of this ordered packing arrangement, the recombinant GABA ...

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Incremental conductance levels of GABA_A receptors in dopaminergic neurones of the rat substantia nigra pars compacta

Cited by 38 publications

References 49 publications

Transcriptional Signatures of Cellular Plasticity in Mice Lacking the α1 Subunit of GABA_AReceptors

Transcriptional Signatures of Cellular Plasticity in Mice Lacking the α1 Subunit of GABA_AReceptors

A Dynamic Role for GABA Receptors on the Firing Pattern of Midbrain Dopaminergic Neurons

GABA Increases both the Conductance and Mean Open Time of Recombinant GABAA Channels Co-expressed with GABARAP

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Incremental conductance levels of GABAA receptors in dopaminergic neurones of the rat substantia nigra pars compacta

Cited by 38 publications

References 49 publications

Transcriptional Signatures of Cellular Plasticity in Mice Lacking the α1 Subunit of GABAAReceptors

Transcriptional Signatures of Cellular Plasticity in Mice Lacking the α1 Subunit of GABAAReceptors

A Dynamic Role for GABA Receptors on the Firing Pattern of Midbrain Dopaminergic Neurons

GABA Increases both the Conductance and Mean Open Time of Recombinant GABAA Channels Co-expressed with GABARAP

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Incremental conductance levels of GABA_A receptors in dopaminergic neurones of the rat substantia nigra pars compacta

Transcriptional Signatures of Cellular Plasticity in Mice Lacking the α1 Subunit of GABA_AReceptors

Transcriptional Signatures of Cellular Plasticity in Mice Lacking the α1 Subunit of GABA_AReceptors