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

Khirug, Stanislav; Yamada, Jun; Afzalov, Ramil; Voipio, Juha; Khiroug, Leonard; Kaila, Kai

doi:10.1523/jneurosci.0908-08.2008

Cited by 264 publications

(306 citation statements)

References 33 publications

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“…Imposing a defined somatic Cl Ϫ load via the patch pipette enables assessment of the efficacy of Cl Ϫ extrusion. As shown previously (Khirug et al, 2005(Khirug et al, , 2008(Khirug et al, , 2010Blaesse et al, 2006;Li et al, 2007;Gauvain et al, 2011), functional expression of KCC2 results in a somatodendritic gradient of [Cl Ϫ ] i , which can be measured as a gradient in E GABA between the somatic and dendritic compartments (⌬E GABA ). Notably, control levels of ⌬E GABA remained unchanged for the experimental duration of 0 -4 h (0 -2 h: Ϫ6.05 Ϯ 0.31 mV/50 m; n ϭ 12 cells; 3-4 h: Ϫ6.28 Ϯ 0.28 mV/50 m; n ϭ 14 cells).…”

Section: Total Block Of Protein Synthesis Does Not Affect Kcc2 Proteimentioning

confidence: 62%

Activity-Dependent Cleavage of the K-Cl Cotransporter KCC2 Mediated by Calcium-Activated Protease Calpain

et al. 2012

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The K-Cl cotransporter KCC2 plays a crucial role in neuronal chloride regulation. In mature central neurons, KCC2 is responsible for the low intracellular Cl Ϫ concentration ([Cl Ϫ ] i ) that forms the basis for hyperpolarizing GABA A receptor-mediated responses. Fast changes in KCC2 function and expression have been observed under various physiological and pathophysiological conditions. Here, we show that the application of protein synthesis inhibitors cycloheximide and emetine to acute rat hippocampal slices have no effect on total KCC2 protein level and K-Cl cotransporter function. Furthermore, blocking constitutive lysosomal degradation with leupeptin did not induce significant changes in KCC2 protein levels. These findings indicate a low basal turnover rate of the total KCC2 protein pool. In the presence of the glutamate receptor agonist NMDA, the total KCC2 protein level decreased to about 30% within 4 h, and this effect was blocked by calpeptin and MDL-28170, inhibitors of the calcium-activated protease calpain. Interictal-like activity induced by incubation of hippocampal slices in an Mg 2ϩ -free solution led to a fast reduction in KCC2-mediated Cl Ϫ transport efficacy in CA1 pyramidal neurons, which was paralleled by a decrease in both total and plasmalemmal KCC2 protein. These effects were blocked by the calpain inhibitor MDL-28170. Taken together, these findings show that calpain activation leads to cleavage of KCC2, thereby modulating GABAergic signaling.

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Section: Total Block Of Protein Synthesis Does Not Affect Kcc2 Proteimentioning

confidence: 62%

Activity-Dependent Cleavage of the K-Cl Cotransporter KCC2 Mediated by Calcium-Activated Protease Calpain

et al. 2012

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“…Previous results indicated a somatodendritic gradient of E GABA in DG PCs (Khirug et al, 2008). We therefore addressed whether dendrite-targeting GABAergic synapses in this brain region are also depolarizing in nature (Fig.…”

Section: Depolarizing Inhibition Is the General Mode Of Gabaergic Sigmentioning

confidence: 90%

Interneurons Provide Circuit-Specific Depolarization and Hyperpolarization

Sauer

Strüber²,

Bartos³

2012

J. Neurosci.

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Perisoma-inhibiting interneurons (PIIs) control fundamental aspects of cortical network function by means of their GABAergic output synapses. However, whether they depolarize or hyperpolarize their target cells in the mature circuitry remains controversial. By using unitary field potential and gramicidin D perforated-patch recordings, we provide evidence that the postsynaptic effect of GABAergic synapses is fundamentally different in two regions of rat hippocampus. Signaling at PII output synapses is hyperpolarizing in CA1 principal cells (PCs) but depolarizing in dentate gyrus (DG) PCs. While the reversal potential of GABA A receptor-mediated currents is identical in both areas, ϳ15 mV more negative resting potentials of DG compared with CA1 PCs underlie the opposing effects of perisomatic GABAergic transmission. Thus, the nature of PII output signaling is circuit-dependent and may therefore contribute differentially to information processing in the two brain areas.

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“…The amplitude and direction of a transmembrane current ( I) depends on the conductance ( G) and on the driving force (DF ) acting on ions passing through this conductance (I ϭ DF ϫ G). Previous studies indicated that Ggaba significantly exceeds Gglu during GDPs and also reported that the onset of Ggaba activation precedes that of Gglu Leinekugel et al, 1997;Bolea et al, 1999;Lamsa et al, 2000;Mohajerani and Cherubini, 2005;Cherubini et al, 2011;Khalilov et al, 2014). However, the DF values for both conductances and their dynamic changes during GDPs remain unknown; this precludes the estimation of currents.…”

Section: Introductionmentioning

confidence: 95%

“…Initially GDPs were described in CA3 pyramidal cells as purely GABA driven events because their reversal potential is close to the reversal potential of the chloride currents mediated by the GABA(A) receptors and their sensitivity to the GABA(A) receptor antagonists (Ben-Ari et al, 1989). However, GDPs are also suppressed by glutamate receptor antagonists, and intracellular blockade of GABA(A) receptors reveals glutamatergic synaptic conductance activated during GDPs Leinekugel et al, 1997;Bolea et al, 1999;Lamsa et al, 2000;Sipilä et al, 2005;Khalilov et al, 2014). These findings have led to a model where neuronal excitation during GDPs is brought about by synergistic excitatory actions of depolarizing GABA and glutamate (BenAri et al, 1997;Khazipov et al, 1997;Leinekugel et al, 1997;Bolea et al, 1999;Cherubini et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…These findings have led to a model where neuronal excitation during GDPs is brought about by synergistic excitatory actions of depolarizing GABA and glutamate (BenAri et al, 1997;Khazipov et al, 1997;Leinekugel et al, 1997;Bolea et al, 1999;Cherubini et al, 2011). On the other hand, blockade of GABA(A) receptors induces hypersynchronous epileptiform discharges indicating that GABA also exerts inhibitory actions in the CA3 network (Khalilov et al, 1997b(Khalilov et al, , 1999Khazipov et al, 1997;Lamsa et al, 2000) and suggesting that depolarizing GABA exerts dual, both excitatory and inhibitory actions in the immature network. The nature of this dualism in the early GABA actions remains unclear, however.…”

Section: Introductionmentioning

confidence: 99%

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Dynamic Changes from Depolarizing to Hyperpolarizing GABAergic Actions during Giant Depolarizing Potentials in the Neonatal Rat Hippocampus

et al. 2015

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During development, GABA exerts depolarizing action on immature neurons and, acting in synergy with glutamate, drives giant depolarizing potentials (GDPs) in the hippocampal network. Yet, blockade of the GABA(A) receptors transforms GDPs to epileptiform discharges suggesting dual, both excitatory and inhibitory, actions of GABA in the immature hippocampal network. However, the nature of this dualism in early GABA actions is poorly understood. Here we characterized the dynamics of synaptic currents mediated by GABA(A) and glutamate receptors through an estimation of the changes in their conductance and driving forces in neonatal rat CA3 pyramidal cells during GDPs. We found that depolarizing GABAergic and glutamatergic currents act in synergy at the GDPs' onset. However, during the peak of the population discharge, the inward synaptic current was essentially mediated by glutamate receptors whereas GABA currents transiently switched their direction from depolarizing to hyperpolarizing as a result of neuronal depolarization above the GABA(A) reversal potential. Thus, the action of GABA on CA3 pyramidal cells dynamically changes during GDPs from excitatory at the GDPs' onset to inhibitory at the GDPs' peak. We propose that the dynamic changes in GABA actions occurring during GDPs enable GABAergic interneurons not only to initiate the discharge of pyramidal cells but also to control excitation in the recurrent CA3 network preventing epileptiform synchronization.

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

Cited by 264 publications

References 33 publications

Activity-Dependent Cleavage of the K-Cl Cotransporter KCC2 Mediated by Calcium-Activated Protease Calpain

Activity-Dependent Cleavage of the K-Cl Cotransporter KCC2 Mediated by Calcium-Activated Protease Calpain

Interneurons Provide Circuit-Specific Depolarization and Hyperpolarization

Dynamic Changes from Depolarizing to Hyperpolarizing GABAergic Actions during Giant Depolarizing Potentials in the Neonatal Rat Hippocampus

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