The slow inhibitory postsynaptic potential in rat hippocampal CA1 neurones is blocked by intracellular injection of QX-314

Nathan, Torben; Jensen, Morten Skovgaard; Lambert, John D. C.

doi:10.1016/0304-3940(90)90865-7

Cited by 153 publications

(111 citation statements)

References 12 publications

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“…To determine whether repetitive whisker stimulation differentially alters the excitatory and inhibitory inputs to L4 neurons, we recorded 10 cells with the sodium channel blocker QX-314 (25 mM) in the pipette. QX-314 also partially blocks calcium and potassium channels (Nathan et al, 1990;Perkins and Wong, 1995;Talbot and Sayer, 1996). However, in previous studies without QX-314, we found that the V m behaved linearly over the ranges studied here Contreras, 2003, 2005), suggesting these voltagedependent currents do not play a large role in mediating whiskerevoked responses.…”

Section: Relative Adaptation Of Excitatory and Inhibitory Synaptic Cocontrasting

confidence: 49%

Balanced Excitation and Inhibition Determine Spike Timing during Frequency Adaptation

Higley¹,

Contreras²

2006

J. Neurosci.

252

244

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In layer 4 (L4) of the rat barrel cortex, a single whisker deflection evokes a stereotyped sequence of excitation followed by inhibition, hypothesized to result in a narrow temporal window for spike output. However, awake rats sweep their whiskers across objects, activating the cortex at frequencies known to induce short-term depression at both excitatory and inhibitory synapses within L4. Although periodic whisker deflection causes a frequency-dependent reduction of the cortical response magnitude, whether this adaptation involves changes in the relative balance of excitation and inhibition and how these changes might impact the proposed narrow window of spike timing in L4 is unknown. Here, we demonstrate for the first time that spike output in L4 is determined precisely by the dynamic interaction of excitatory and inhibitory conductances. Furthermore, we show that periodic whisker deflection results in balanced adaptation of the magnitude and timing of excitatory and inhibitory input to L4 neurons. This balanced adaptation mediates a reduction in spike output while preserving the narrow time window of spike generation, suggesting that L4 circuits are calibrated to maintain relative levels of excitation and inhibition across varying magnitudes of input.

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Section: Relative Adaptation Of Excitatory and Inhibitory Synaptic Cocontrasting

confidence: 49%

Balanced Excitation and Inhibition Determine Spike Timing during Frequency Adaptation

Higley¹,

Contreras²

2006

J. Neurosci.

252

244

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“…Glucuronate salts were used because the permeability of the anion through GABA A channels should be small because of its restricted, bulky conformation. 5-N-(2,6-dimethylphenylcarbamoylmethyl)-triethylammonium bromide (QX314) was added to the intracellular solution to block Na ϩ and K ϩ currents (Connors and Prince, 1982;Nathan et al, 1990;Colling and Wheal, 1994). The Br Ϫ salt was used because in initial experiments the block of action potentials was faster and more complete with Br Ϫ than with the Cl Ϫ salt.…”

Section: Methodsmentioning

confidence: 99%

A Furosemide-Sensitive K⁺–Cl⁻Cotransporter Counteracts Intracellular Cl⁻Accumulation and Depletion in Cultured Rat Midbrain Neurons

1999

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Efficacy of postsynaptic inhibition through GABA A receptors in the mammalian brain depends on the maintenance of a Cl Ϫ gradient for hyperpolarizing Cl Ϫ currents. We have taken advantage of the reduced complexity under which Cl Ϫ regulation can be investigated in cultured neurons as opposed to neurons in other in vitro preparations of the mammalian brain. GABA is the main inhibitory transmitter in the mammalian brain. The dominant effect of GABA A receptor activation is a hyperpolarization caused by C l Ϫ flux into the cell (for review, see Sivilotti and Nistri, 1991;Kaila, 1994;Thompson, 1994). However, the direction of the C l Ϫ flux depends on the C l Ϫ gradient across the membrane. Indeed, GABA A receptor-mediated hyperpolarizing and /or depolarizing postsynaptic potentials have been observed (for review, see Kaila, 1994;Thompson, 1994). Some findings suggest variations in intracellular [C l Ϫ ] between different neurons and even a distinct C l Ϫ distribution in different compartments of a single neuron (Misgeld et al., 1986). Depolarizing GABA A responses, however, can be caused by bicarbonate efflux in combination with C l Ϫ influx or combined Cl Ϫ and HCO 3 Ϫ efflux (Grover et al., 1993;Kaila, 1994;Thompson, 1994;Staley et al., 1995;Perkins and Wong, 1996;Kaila et al., 1997). To be able to predict the direction of C l Ϫ currents flowing during GABA A receptor-mediated inhibition it is essential to understand the regulation of C l Ϫ homeostasis that provides the transmembrane gradient.A recently cloned K ϩ -Cl Ϫ cotransporter gene (KCC2) represents a perfect candidate for the regulation of neuronal Cl Ϫ homeostasis (Payne et al., 1996). In contrast to the ubiquitous presence of the K ϩ -Cl Ϫ cotransporter KCC1, expression of the K ϩ -Cl Ϫ cotransporter KCC2 is detected in C NS only and seems to be neuron specific. KCC2 is also distinct from KCC1 in that KCC2 is not involved in cell volume regulation and not activated by osmotic changes. Furthermore, KCC2 has a high affinity for extracellular K ϩ ions. The properties of KCC2 allow the regulation of [Cl Ϫ ] i to maintain Cl Ϫ gradients for hyperpolarizing GABAergic inhibition. Thermodynamic considerations predict that the electroneutral K ϩ -Cl Ϫ cotransporter KCC2 operates near equilibrium under physiological ionic conditions. Depending on [Cl Ϫ ] i and [K ϩ ] o (Payne, 1997), the transport will extrude or accumulate Cl Ϫ .The functional role of a particular Cl Ϫ transport system in neuronal Cl Ϫ regulation is difficult to establish in studies using integral preparations such as brain slices. One complicating factor is the presence of HCO 3 Ϫ anions. The HCO 3 Ϫ permeability of the GABA A channel (Bormann, 1988;Fatima-Shad and Barry, 1993) impedes conclusions toward actual [Cl Ϫ ] i if they are calculated from reversal potentials of GABA A receptor-mediated anion currents. Furthermore, a HCO 3 Ϫ /Cl Ϫ exchanger (RaleySusman et al., 1993) may well interfere (Chesler, 1990), and pH changes that result from manipulations of [HCO 3 Ϫ ] o strongly affect neur...

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“…First, we analyzed the paired-pulse glutamatergic depression (cf., Kang, 1995;Gil et al, 1997) by using electrodes containing KCl + QX-314. In addition to reducing current through voltage-gated Na + channels (Connors and Prince, 1982), QX-314 blocks postsynaptic GABA B receptor-mediated conductances (Nathan et al, 1990) thus allowing us to assess the sole presumptive contribution of presynaptic GABA B receptors located on glutamatergic terminals to paired-pulse depression. The ASCF used in these experiments contained picrotoxin to block GABA A receptors and CPP + 4 mM Mg 2+ to abolish NMDA receptor-mediated currents, while the stimulating electrode was placed in the white matter.…”

Section: Paired-pulse Depression Is Reduced In the Epileptic Wag/rij mentioning

confidence: 99%

“…Recordings were made with K-acetate + QX-314-filled electrodes during superfusion of ASCF containing the glutamatergic antagonists CPP and CNQX. Since QX-314 abolishes responses caused by activation of postsynaptic GABA B receptors (Nathan et al, 1990), the stimulus-induced responses recorded under these experimental conditions represented isolated GABA A receptor-mediated IPSPs (cf., Fukuda et al, 1993;Deisz, 1999). In addition, since QX-314 attenuates I h (Perkins and Wong, 1995), we could analyze these IPSPs in their reversed form by holding the membrane potential at values more negative than − 90 mV.…”

Section: Paired-pulse Depression Is Reduced In the Epileptic Wag/rij mentioning

confidence: 99%

Reduced GABAB receptor subunit expression and paired-pulse depression in a genetic model of absence seizures

Merlo

Mollinari

Inaba

et al. 2007

Neurobiology of Disease

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Neocortical networks play a major role in the genesis of generalized spike-and-wave (SW) discharges associated with absence seizures in humans and in animal models, including genetically predisposed WAG/Rij rats. Here, we tested the hypothesis that alterations in GABA B receptors contribute to neocortical hyperexcitability in these animals. By using Real-Time PCR we found that mRNA levels for most GABA B(1) subunits are diminished in epileptic WAG/Rij neocortex as compared with age-matched non-epileptic controls (NEC), whereas GABA B(2) mRNA is unchanged. Next, we investigated the cellular distribution of GABA B(1) and GABA B(2) subunits by confocal microscopy and discovered that GABA B(1) subunits fail to localize in the distal dendrites of WAG/Rij neocortical pyramidal cells. Intracellular recordings from neocortical cells in an in vitro slice preparation demonstrated reduced paired-pulse depression of pharmacologically isolated excitatory and inhibitory responses in epileptic WAG/Rij rats as compared with NECs; moreover, paired-pulse depression in NEC slices was diminished by a GABA B receptor antagonist to a greater extent than in WAG/Rij rats further suggesting GABA B receptor dysfunction. In conclusion, our data identify changes in GABA B receptor subunit expression and distribution along with decreased paired-pulse depression in epileptic WAG/Rij rat neocortex. We propose that these alterations may contribute to neocortical hyperexcitability and thus to SW generation in absence epilepsy.

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The slow inhibitory postsynaptic potential in rat hippocampal CA1 neurones is blocked by intracellular injection of QX-314

Cited by 153 publications

References 12 publications

Balanced Excitation and Inhibition Determine Spike Timing during Frequency Adaptation

Balanced Excitation and Inhibition Determine Spike Timing during Frequency Adaptation

A Furosemide-Sensitive K⁺–Cl⁻Cotransporter Counteracts Intracellular Cl⁻Accumulation and Depletion in Cultured Rat Midbrain Neurons

Reduced GABAB receptor subunit expression and paired-pulse depression in a genetic model of absence seizures

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The slow inhibitory postsynaptic potential in rat hippocampal CA1 neurones is blocked by intracellular injection of QX-314

Cited by 153 publications

References 12 publications

Balanced Excitation and Inhibition Determine Spike Timing during Frequency Adaptation

Balanced Excitation and Inhibition Determine Spike Timing during Frequency Adaptation

A Furosemide-Sensitive K+–Cl−Cotransporter Counteracts Intracellular Cl−Accumulation and Depletion in Cultured Rat Midbrain Neurons

Reduced GABAB receptor subunit expression and paired-pulse depression in a genetic model of absence seizures

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A Furosemide-Sensitive K⁺–Cl⁻Cotransporter Counteracts Intracellular Cl⁻Accumulation and Depletion in Cultured Rat Midbrain Neurons