Activity-dependent depression of monosynaptic fast IPSCs in hippocampus: contributions from reductions in chloride driving force and conductance

Ling, Douglas S.F.; Benardo, Larry S.

doi:10.1016/0006-8993(94)01298-v

Cited by 33 publications

(19 citation statements)

References 17 publications

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“…2 D-F ). At higher frequencies, we did not observe significant differences between WT and KO (2 Hz: WT, 42.4 Ϯ 3.5%, n ϭ 14; KO, 48.9 Ϯ 4.3%, n ϭ 15, p Ͼ 0.05; 5 Hz: WT, 58.1 Ϯ 4.0%, n ϭ 8; KO, 57.5 Ϯ 4.9%, n ϭ 9, p Ͼ 0.05, t test), consistent with the idea that the reduction of presynaptic release is the main cause for the depression at higher frequencies (Ling and Benardo, 1995). These experiments demonstrate that ClC-2 accelerates chloride extrusion if the cell is strongly loaded with chloride.…”

Section: Does Clc-2 Assist Chloride Extrusion?supporting

confidence: 82%

ClC-2 Voltage-Gated Channels Constitute Part of the Background Conductance and Assist Chloride Extrusion

Rinke¹,

Artmann²,

Stein³

2010

J. Neurosci.

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The function of voltage-gated chloride channels in neurons is essentially unknown. The voltage-gated chloride channel ClC-2 mediates a chloride current in pyramidal cells of the hippocampus. We directly show that ClC-2 assists chloride extrusion after high chloride load. Furthermore, the loss of this chloride channel leads to a dramatic increase of the input resistance of CA1 pyramidal cells, making these cells more excitable. Surprisingly, basal synaptic transmission, as judged from recordings of field EPSPs, was decreased. This difference was eliminated when GABAergic inhibition was blocked. Recordings from hippocampal interneurons revealed ClC-2-mediated currents in a subset of these cells. An observed increase in GABAergic inhibition could thus be explained by an increase in the excitability of interneurons, caused by the loss of ClC-2. Together, we suggest a dual role for ClC-2 in neurons, providing an additional efflux pathway for chloride and constituting a substantial part of the background conductance, which regulates excitability. In ClC-2 knock-out mice, an increased inhibition seemingly balances the hyperexcitability of the network and thereby prevents epilepsy.

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Section: Does Clc-2 Assist Chloride Extrusion?supporting

confidence: 82%

ClC-2 Voltage-Gated Channels Constitute Part of the Background Conductance and Assist Chloride Extrusion

Rinke¹,

Artmann²,

Stein³

2010

J. Neurosci.

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“…There are several possible explanations for this observation. A reduced ability to recover from desensitization, 10 an alteration in the chloride equilibrium potential and/or altered activity of chloride exchange mechanisms, 11 and alterations in phosphorylation state 12,13 could contribute to what appears to be a cumulative effect of brief GABA applications. The functional significance of this observation may be manifested when the GABAergic inputs are pulsatile as opposed to tonic in nature.…”

Section: Discussionmentioning

confidence: 99%

Responses to GABAA receptor activation are altered in NTS neurons isolated from chronic hypoxic rats

2004

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Abstract-The inhibitory amino acid GABA is a potent modulator of the spontaneous discharge and the responses to afferent inputs of neurons in the nucleus of the solitary tract (NTS). To determine if responses to activation of GABA A receptors are altered in hypertension, GABA A receptor-evoked whole cell currents were measured in enzymatically dispersed NTS neurons from 33 normotensive (NT, 109Ϯ4 mm Hg, nϭ7) and 24 hypertensive (HT, 167Ϯ5 mm Hg, nϭ24) rats. GABA A receptor-evoked currents reversed at the calculated equilibrium potential for chloride and were blocked by bicuculline (nϭ6). Membrane capacitance was the same in neurons from NT (7.5Ϯ0.6 pF, nϭ62) and HT (6.8Ϯ0.6 pF, nϭ51) rats. The EC 50 for peak GABA-evoked currents cells was significantly greater in neurons from HT (21.0Ϯ2.6 mol/L, nϭ16) compared with NT rats (13.0Ϯ1.8 mol/L, nϭ14, Pϭ0.01). The EC 50 of neurons exhibiting DiA labeling of presumptive aortic nerve terminals was no different than that observed in the nonlabeled cells (19.0Ϯ4.9 mol/L, nϭ4). The time constant for desensitization of GABA A -evoked currents was the same in neurons from HT (4.5Ϯ0.3 seconds, nϭ17) and NT rats (3.8Ϯ0.3 seconds, nϭ17, PϾ0.05). Repetitive pulse application of GABA revealed a more rapid decline in the evoked current in neurons from HT compared with NT rats. The amplitude of the 5th pulse of GABA (5-second duration, 2-second interval) was 21Ϯ2% the amplitude of the 1st pulse in NT rats (nϭ10) and 14Ϯ2% in HT rats (nϭ11, PϽ0.05). These alterations in GABA A -receptor evoked currents could render the neurons less sensitive to GABA A receptor inhibition and influence afferent integration by NTS neurons in HT. [2][3][4] Within the NTS, activation of GABA A receptors inhibits virtually all neurons tested and results in an increase in arterial pressure, heart rate, and sympathetic outflow, effects consistent with inhibitory modulation of arterial baroreceptor reflexes. 1 The function of GABA A receptors has been shown to be modulated by a variety of factors. Receptor number, subunit composition, and phosphorylation state are but a few of the ways that GABA receptor function can be altered after chronic exposure to alcohol, barbiturates, benzodiazepines, and GABA itself. [2][3][4] Alterations in the responses of NTS neurons to GABA A receptor activation could result in alterations in the integration of afferent inputs, reflex function, and resting cardiovascular parameters. The goal of the current study was to determine if the responses of isolated NTS neurons to activation of GABA A receptors are altered in hypertension. Methods GeneralSuccessful experiments were performed on adult (1 to 3 months), male Sprague-Dawley rats (375 to 500 g, Charles River Laboratories or Harlan Sprague-Dawley Inc). Rats were housed 2 per cage in a fully accredited (Association for Assessment and Accreditation of Laboratory Animal Care and the United States Department of Agriculture) laboratory animal room with free access to food and water. All rats were given at least 1 week to acclimat...

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“…The general concept that GABA-induced chloride flux can substantially alter [Cl 2 ] i has been proposed and supported by several studies (Huguenard and Alger, 1986;Akaike et al, 1987;Kaila et al, 1989;Thompson and Gähwiler, 1989;Ling and Benardo, 1995;Kuner and Augustine, 2000;De Fazio and Hablitz, 2001;Wagner et al, 2001;Isomura et al, 2003;Berglund et al, 2008). As an additional mechanism, network driven K 1 accumulation is thought to enhance the depolarizing response by both direct membrane depolarization and a reduction of Cl 2 extrusion (McCarren and Alger, 1985;Kaila et al, 1997;Bazhenov et al, 2008; see note added in proof; see also Perkins and Wong, 1996;Perkins, 1999).…”

Section: Accumulation and Gabaergic Depolarizationmentioning

confidence: 93%

Activity‐dependent intracellular chloride accumulation and diffusion controls GABA_A receptor‐mediated synaptic transmission

et al. 2011

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In the CNS, prolonged activation of GABA(A) receptors (GABA(A)Rs) has been shown to evoke biphasic postsynaptic responses, consisting of an initial hyperpolarization followed by a depolarization. A potential mechanism underlying the depolarization is an acute chloride (Cl(-)) accumulation resulting in a shift of the GABA(A) reversal potential (E(GABA)). The amount of GABA-evoked Cl(-) accumulation and accompanying depolarization depends on presynaptic and postsynaptic properties of GABAergic transmission, as well as on cellular morphology and regulation of Cl(-) intracellular concentration ([Cl(-)](i)). To analyze the influence of these factors on the Cl(-) and voltage behavior, we studied spatiotemporal dynamics of activity-dependent [Cl(-)](i) changes in multicompartmental models of hippocampal cells based on realistic morphological data. Simulated Cl(-) influx through GABA(A) Rs was able to exceed physiological Cl(-) extrusion rates thereby evoking HCO(3)(-) -dependent E(GABA) shift and depolarizing responses. Depolarizations were observed in spite of GABA(A) receptor desensitization. The amplitude of the depolarization was frequency-dependent and determined by intracellular Cl(-) accumulation. Changes in the dendritic diameter and in the speed of GABA clearance in the synaptic cleft were significant sources of depolarization variability. In morphologically reconstructed granule cells subjected to an intense GABAergic background activity, dendritic inhibition was more affected by accumulation of intracellular Cl(-) than somatic inhibition. Interestingly, E(GABA) changes induced by activation of a single dendritic synapse propagated beyond the site of Cl(-) influx and affected neighboring synapses. The simulations suggest that E(GABA) may differ even along a single dendrite supporting the idea that it is necessary to assign E(GABA) to a given GABAergic input and not to a given neuron.

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Activity-dependent depression of monosynaptic fast IPSCs in hippocampus: contributions from reductions in chloride driving force and conductance

Cited by 33 publications

References 17 publications

ClC-2 Voltage-Gated Channels Constitute Part of the Background Conductance and Assist Chloride Extrusion

ClC-2 Voltage-Gated Channels Constitute Part of the Background Conductance and Assist Chloride Extrusion

Responses to GABAA receptor activation are altered in NTS neurons isolated from chronic hypoxic rats

Activity‐dependent intracellular chloride accumulation and diffusion controls GABA_A receptor‐mediated synaptic transmission

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Activity-dependent depression of monosynaptic fast IPSCs in hippocampus: contributions from reductions in chloride driving force and conductance

Cited by 33 publications

References 17 publications

ClC-2 Voltage-Gated Channels Constitute Part of the Background Conductance and Assist Chloride Extrusion

ClC-2 Voltage-Gated Channels Constitute Part of the Background Conductance and Assist Chloride Extrusion

Responses to GABAA receptor activation are altered in NTS neurons isolated from chronic hypoxic rats

Activity‐dependent intracellular chloride accumulation and diffusion controls GABAA receptor‐mediated synaptic transmission

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Activity‐dependent intracellular chloride accumulation and diffusion controls GABA_A receptor‐mediated synaptic transmission