Effects of volatile anesthetics on the kinetics of inhibitory postsynaptic currents in cultured rat hippocampal neurons

1993 ◽  
Vol 70 (4) ◽  
pp. 1339-1349 ◽  
Author(s):  
M. V. Jones ◽  
N. L. Harrison
Keyword(s):  
Charge Transfer ◽  
Gabaa Receptor ◽  
Hippocampal Neurons ◽  
Slow Component ◽  
Volatile Anesthetics ◽  
Fast Component ◽  
Synaptic Inhibition ◽  
Inhibitory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Kinetics Of

1. The effects of the volatile anesthetics enflurane, halothane, and isoflurane on gamma-aminobutyric acid (GABA) receptor-mediated inhibitory postsynaptic currents (IPSCs) were studied in cultured rat hippocampal neurons. The experimental concentrations of anesthetics were measured directly using gas chromatography. All three anesthetics increased the overall duration of IPSCs, measured as the time to half-decay (T1/2). Clinically effective concentrations of anesthetics [between 0.5 and 1.5 times MAC (minimum alveolar concentration)] produced between 100 and 400% increases in T1/2. These effects were fully reversible, and did not involve alterations in the reversal potential for the IPSC (EIPSC). 2. The decay of the IPSC was fitted as a sum of two exponential functions, yielding a fast component (tau fast = 20 ms), and a slow component (tau slow = 77 ms), such that the fast component accounted for 79% of the IPSC amplitude and 52% of the total charge transfer. All three anesthetics produced concentration-related increases in the amplitude and charge transfer of the slow component, while simultaneously decreasing the amplitude and charge transfer of the fast component. Thus T1/2 approximated tau fast under control conditions, but approximated tau slow in the presence of the anesthetics. 3. Varying the calcium chelating agents in the recording pipettes had no effect on the quality or magnitude of alterations in IPSC kinetics produced by halothane, suggesting that variations in intracellular calcium levels are not required for the effect of halothane on the time course of the IPSC. 4. The (+)-stereoisomer of isoflurane produced greater increases in the duration of the IPSC than the (-)-isomer when applied at approximately equal concentrations, suggesting that there is a structurally selective site of interaction for isoflurane that modulates the GABAA receptor. 5. These results suggest that the previously shown abilities of volatile anesthetics to potentiate responses to exogenously applied GABA and to prolong the duration of GABA-mediated synaptic inhibition may be due to an alteration in the gating kinetics of the GABAA receptor/channel complex. Prolongation of synaptic inhibition in the CNS is consistent with the physiological effects that accompany anesthesia and may contribute to the mechanism of anesthetic action.

GABAA Receptor β3 Subunit Deletion Decreases α2/3 Subunits and IPSC Duration

2003 ◽  
Vol 89 (1) ◽  
pp. 128-134 ◽  
Author(s):  
Epolia Ramadan ◽  
Zhanyan Fu ◽  
Gabriele Losi ◽  
Gregg E. Homanics ◽  
Joseph H. Neale ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Cortical Neurons ◽  
Behavioral Deficits ◽  
Inhibitory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Surface Staining ◽  
Α1 Subunit

Deletion of the β3 subunit of the GABAA receptor produces severe behavioral deficits and epilepsy. GABAA receptor-mediated miniature inhibitory postsynaptic currents (mIPSCs) in cortical neurons in cultures from β3 −/− mice were significantly faster than those in β3 +/+ mice and were more prolonged by zolpidem. Surface staining revealed that the number of β2/3, α2, and α3 (but not of α1) subunit-expressing neurons and the intensity of subunit clusters were significantly reduced in β3 −/− mice. Transfection of β3 −/− neurons with β3 cDNA restored β2/3, α2, and α3 subunits immunostaining and slowed mIPSCs decay. We show that the deletion of the β3 subunit causes the loss of a subset of GABAA receptors with α2 and α3 subunits while leaving a receptor population containing predominantly α1 subunit with fast spontaneous IPSC decay and increased zolpidem sensitivity.

Prolongation of Hippocampal Miniature Inhibitory Postsynaptic Currents in Mice Lacking the GABAA Receptor α1 Subunit

2002 ◽  
Vol 88 (6) ◽  
pp. 3208-3217 ◽  
Author(s):  
Peter A. Goldstein ◽  
Frank P. Elsen ◽  
Shui-Wang Ying ◽  
Carolyn Ferguson ◽  
Gregg E. Homanics ◽  
...  
Keyword(s):  
Pyramidal Cells ◽  
Fluctuation Analysis ◽  
Α Subunit ◽  
Knock Out ◽  
Inhibitory Postsynaptic Currents ◽  
Ca1 Pyramidal Cells ◽  
Postsynaptic Currents ◽  
Decay Times ◽  
Kinetics Of ◽  
Α1 Subunit

GABAA receptors (GABAA-Rs) are pentameric structures consisting of two α, two β, and one γ subunit. The α subunit influences agonist efficacy, benzodiazepine pharmacology, and kinetics of activation/deactivation. To investigate the contribution of the α1 subunit to native GABAA-Rs, we analyzed miniature inhibitory postsynaptic currents (mIPSCs) in CA1 hippocampal pyramidal cells and interneurons from wild-type (WT) and α1 subunit knock-out (α1 KO) mice. mIPSCs recorded from interneurons and pyramidal cells obtained from α1 KO mice were detected less frequently, were smaller in amplitude, and decayed more slowly than mIPSCs recorded in neurons from WT mice. The effect of zolpidem was examined in view of its reported selectivity for receptors containing the α1 subunit. In interneurons and pyramidal cells from WT mice, zolpidem significantly increased mIPSC frequency, prolonged mIPSC decay, and increased mIPSC amplitude; those effects were diminished or absent in neurons from α1 KO mice. Nonstationary fluctuation analysis of mIPSCs indicated that the zolpidem-induced increase in mIPSC amplitude was associated with an increase in the number of open receptors rather than a change in the unitary conductance of individual channels. These data indicate that the α1 subunit is present at synapses on WT interneurons and pyramidal cells, although differences in mIPSC decay times and zolpidem sensitivity suggest that the degree to which the α1 subunit is functionally expressed at synapses on CA1 interneurons may be greater than that at synapses on CA1 pyramidal cells.

Agent-selective Effects of Volatile Anesthetics on GABAAReceptor–mediated Synaptic Inhibition in Hippocampal Interneurons

2001 ◽  
Vol 94 (2) ◽  
pp. 340-347 ◽  
Author(s):  
Koichi Nishikawa ◽  
M. Bruce MacIver
Keyword(s):  
Gabaa Receptor ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Volatile Anesthetics ◽  
Stratum Radiatum ◽  
Synaptic Inhibition ◽  
Gamma Aminobutyric Acid ◽  
Ca1 Region ◽  
Whole Cell Patch Clamp ◽  
Cortical Regions

Background A relatively small number of inhibitory interneurons can control the excitability and synchronization of large numbers of pyramidal cells in hippocampus and other cortical regions. Thus, anesthetic modulation of interneurons could play an important role for the maintenance of anesthesia. The aim of this study was to compare effects produced by volatile anesthetics on inhibitory postsynaptic currents (IPSCs) of rat hippocampal interneurons. Methods Pharmacologically isolated gamma-aminobutyric acid type A (GABAA) receptor-mediated IPSCs were recorded with whole cell patch-clamp techniques in visually identified interneurons of rat hippocampal slices. Neurons located in the stratum radiatum-lacunosum moleculare of the CA1 region were studied. The effects of clinically relevant concentrations (1.0 rat minimum alveolar concentration) of halothane, enflurane, isoflurane, and sevoflurane were compared on kinetics of both stimulus-evoked and spontaneous GABAA receptor-mediated IPSCs in interneurons. Results Halothane (1.2 vol% approximately 0.35 mm), enflurane (2.2 vol% approximately 0.60 mm), isoflurane (1.4 vol% approximately 0.50 mm), and sevoflurane (2.7 vol% approximately 0.40 mm) preferentially depressed evoked IPSC amplitudes to 79.8 +/- 9.3% of control (n = 5), 38.2 +/- 8.6% (n = 6), 52.4 +/- 8.4% (n = 5), and 46.1 +/- 16.0% (n = 8), respectively. In addition, all anesthetics differentially prolonged the decay time constant of evoked IPSCs to 290.1 +/- 33.2% of control, 423.6 +/- 47.1, 277.0 +/- 32.2, and 529 +/- 48.5%, respectively. The frequencies of spontaneous IPSCs were increased by all anesthetics (twofold to threefold). Thus, the total negative charge transfer mediated by GABAA receptors between synaptically connected interneurons was enhanced by all anesthetics. Conclusions Volatile anesthetics differentially enhanced GABAA receptor-mediated synaptic inhibition in rat hippocampal interneurons, suggesting that hippocampal interneuron circuits are depressed by these anesthetics in an agent-specific manner.

scholarly journals Characterization of a Novel Tonic γ-Aminobutyric AcidA Receptor-Mediated Inhibition in Magnocellular Neurosecretory Neurons and Its Modulation by Glia

Endocrinology ◽  
2006 ◽  
Vol 147 (8) ◽  
pp. 3746-3760 ◽  
Author(s):  
Jin Bong Park ◽  
Silvia Skalska ◽  
Javier E. Stern
Keyword(s):  
Gabaa Receptor ◽  
Gabaa Receptors ◽  
Neuronal Excitability ◽  
Tonic Inhibition ◽  
Synaptic Activity ◽  
Inhibitory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Gaba Transporters ◽  
Neurosecretory Neurons ◽  
Vasopressin Neurons

In addition to mediating conventional quantal synaptic transmission (also known as phasic inhibition), γ-aminobutyric acidA (GABAA) receptors have been recently shown to underlie a slower, persistent form of inhibition (tonic inhibition). Using patch-clamp electrophysiology and immunohistochemistry, we addressed here whether a GABAA receptor-mediated tonic inhibition is present in supraoptic nucleus (SON) neurosecretory neurons; identified key modulatory mechanisms, including the role of glia; and determined its functional role in controlling SON neuronal excitability. Besides blocking GABAA-mediated inhibitory postsynaptic currents, the GABAA receptor blockers bicuculline and picrotoxin caused an outward shift in the holding current (Itonic), both in oxytocin and vasopressin neurons. Conversely, the high-affinity antagonist gabazine selectively blocked inhibitory postsynaptic currents. Under basal conditions, Itonic was independent on the degree of synaptic activity but was strongly modulated by the activity GABA transporters (GATs), mostly the GAT3 isoform, found here to be localized in SON glial cells/processes. Extracellular activation of GABAergic afferents evoked a small gabazine-insensitive, bicuculline-sensitive current, which was enhanced by GAT blockade. These results suggest that Itonic may be activated by spillover of GABA during conditions of strong and/or synchronous synaptic activity. Blockade of Itonic increased input resistance, induced membrane depolarization and firing activity, and enhanced the input-output function of SON neurons. In summary, our results indicate that GABAA receptors, possibly of different molecular configuration and subcellular distribution, mediate synaptic and tonic inhibition in SON neurons. The latter inhibitory modality plays a major role in modulating SON neuronal excitability, and its efficacy is modulated by the activity of glial GATs.

Evoked inhibitory postsynaptic currents in the dynamics of development of cultured hippocampal neurons of rats

1999 ◽  
Vol 31 (5) ◽  
pp. 304-309 ◽  
Author(s):  
E. V. Isaeva ◽  
V. G. Sidorenko ◽  
S. A. Fedulova ◽  
N. S. Veselovskii
Keyword(s):  
Hippocampal Neurons ◽  
Inhibitory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Cultured Hippocampal Neurons

scholarly journals Immunoglobulins from amyotrophic lateral sclerosis patients enhance the frequency of glycine-mediated spontaneous inhibitory postsynaptic currents in rat hypoglossal motoneurons

2007 ◽  
Vol 59 (4) ◽  
pp. 251-255 ◽  
Author(s):  
P.R. Andjus
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Hippocampal Neurons ◽  
Spontaneous Release ◽  
Hypoglossal Motoneurons ◽  
Inhibitory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Als Patients ◽  
Brain Stem Slices ◽  
Ca2 Channels ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating, still incurable neurological disorder affecting upper and lower motoneurons. Passive transfer of the disease occurs when immunoglobulins from ALS patients are injected into experimental animals. It is suggested that ALS IgGs cause excitotoxicity by acting on voltage-gated Ca2+ channels. We reported previously that ALS IgGs increase spontaneous release of glutamate in hippocampal neurons. Since these cells are not normally affected in ALS, we here studied the effect of ALS IgGs on hypoglossal motoneurons in rat brain-stem slices. The frequency of spontaneous glycine-mediated inhibitory postsynaptic currents (sIPSCs) was augmented, but not that of miniature ones (mIPSCs), thus pointing to an indirect effect on release.

scholarly journals Plasticity of spontaneous excitatory and inhibitory synaptic activity in morphologically defined vestibular nuclei neurons during early vestibular compensation

2012 ◽  
Vol 107 (1) ◽  
pp. 29-41 ◽  
Author(s):  
Mei Shao ◽  
June C. Hirsch ◽  
Kenna D. Peusner
Keyword(s):  
Charge Transfer ◽  
Brain Slices ◽  
Vestibular Nuclei ◽  
Synaptic Activity ◽  
Vestibular Compensation ◽  
Early Recovery ◽  
Inhibitory Postsynaptic Currents ◽  
Principal Cells ◽  
Postsynaptic Currents ◽  
Lesion Side

After unilateral peripheral vestibular lesions, the brain plasticity underlying early recovery from the static symptoms is not fully understood. Principal cells of the chick tangential nucleus offer a subset of morphologically defined vestibular nuclei neurons to study functional changes after vestibular lesions. Chickens show posture and balance deficits immediately after unilateral vestibular ganglionectomy (UVG), but by 3 days most subjects begin to recover, although some remain uncompensated. With the use of whole cell voltage-clamp, spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) and miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs) were recorded from principal cells in brain slices 1 and 3 days after UVG. One day after UVG, sEPSC frequency increased on the lesion side and remained elevated at 3 days in uncompensated chickens only. Also by 3 days, sIPSC frequency increased on the lesion side in all operated chickens due to major increases in GABAergic events. Significant change also occurred in decay time of the events. To determine whether fluctuations in frequency and kinetics influenced overall excitatory or inhibitory synaptic drive, synaptic charge transfer was calculated. Principal cells showed significant increase in excitatory synaptic charge transfer only on the lesion side of uncompensated chickens. Thus compensation continues when synaptic charge transfer is in balance bilaterally. Furthermore, excessive excitatory drive in principal cells on the lesion side may prevent vestibular compensation. Altogether, this work is important for it defines the time course and excitatory and inhibitory nature of changing spontaneous synaptic inputs to a morphologically defined subset of vestibular nuclei neurons during critical early stages of recovery after UVG.

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