Modulation of decay kinetics and frequency of GABAA receptor-mediated spontaneous inhibitory postsynaptic currents in hippocampal neurons

Neuroscience ◽  
1992 ◽  
Vol 49 (1) ◽  
pp. 13-32 ◽  
Author(s):  
T.S. Otis ◽  
I. Mody
Keyword(s):  
Gabaa Receptor ◽  
Hippocampal Neurons ◽  
Decay Kinetics ◽  
Inhibitory Postsynaptic Currents ◽  
Postsynaptic Currents

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.

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

Ca(2+)-dependent plasticity of miniature inhibitory postsynaptic currents after amputation of dendrites in central neurons

1995 ◽  
Vol 73 (5) ◽  
pp. 1763-1773 ◽  
Author(s):  
I. Soltesz ◽  
I. Mody
Keyword(s):  
Granule Cells ◽  
Dendritic Tree ◽  
Granule Cell Layer ◽  
Na Channel ◽  
Decay Kinetics ◽  
Whole Cell ◽  
Inhibitory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Population Spikes ◽  
Whole Cell Recordings

1. The effects of cutting off the bulk (> 2/3) of the dendritic tree (dendrotomy) on GABAergic miniature inhibitory postsynaptic currents (mIPCSs) were studied in granule cells of the adult rat dentate gyrus in 400-microns-thick slices in vitro. 2. After dendrotomy carried out in warm (32 degrees C) control artificial cerebrospinal fluid (ACSF), only small antidromic population spikes could be evoked in the granule cell layer, and no viable whole cell recordings could be obtained. However, when dendrotomy was performed in cold (8-10 degrees C) control ACSF, the amplitude of the antidromic population spikes increased, and stable whole cell recordings became possible. 3. Whole cell recordings, with CsCl-filled pipettes, from granule cells dendrotomized in cold control ACSF, revealed significant alterations, lasting > 10 h, in the decay kinetics of mIPSACs. The change consisted of a calcium-dependent transformation of the normal, single exponential decay into a prolonged double exponential that effectively increased the charge transferred by the synaptic events (the total area of the currents) by 67%. When 30 mM 1,2 bis-(2-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA) was included in the pipette, the changes in the mIPSCs decay kinetics could still be observed after dendrotomy, indicating that the maintenance phase of this plasticity did not depend on elevated intracellular calcium levels. 4. Viable whole cell recordings could also be obtained in dendrotomized granule cells when the amputation of dendrites was carried out at 32 degrees C after incubation for 2 h with the cell-permeant Ca2+ chelator, BAPTA-AM (50 microM), or the cutting process was done in an ACSF containing either a combination of excitatory amino acid receptor antagonists 2-amino-5-phosphonovaleric acid (APV; 25 microM) + 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM), a blocker of intracellular Ca2+ release dantrolene-Na (20 microM), or the voltage-gated Na+ channel blocker tetrodotoxin (TTX; 1 microM). 5. After dendrotomy in BAPTA-AM, APV + CNQX, APV + CNQX + TTX, and/or dantrolene, the changes in decay kinetics were prevented, indicating that a rise in intracellular Ca2+ concentration plays a pivotal role in this plasticity. 6. Computer simulations of mIPSCs suggested that changes in single channel kinetics alone can, in principle, account for the Ca(2+)-dependent changes in mIPSC decay kinetics. 7. These findings are consistent with a lasting Ca(2+)-dependent increase in gamma-aminobutyric acid-A (GABAA) receptor function in cells that survive physical injury to their dendrites.

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.

Hippocampal CA1 lacunosum-moleculare interneurons: comparison of effects of anoxia on excitatory and inhibitory postsynaptic currents

1995 ◽  
Vol 74 (5) ◽  
pp. 2138-2149 ◽  
Author(s):  
R. Khazipov ◽  
P. Congar ◽  
Y. Ben-Ari
Keyword(s):  
Gabaa Receptor ◽  
Reversal Potential ◽  
Pyramidal Cells ◽  
Gabab Receptors ◽  
Stratum Radiatum ◽  
Patch Clamp Technique ◽  
Positive Shift ◽  
Inhibitory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Presynaptic Mechanisms

1. The effects of anoxia on excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs, respectively) evoked by electrical stimulation in the stratum radiatum were studied in morphologically and electrophysiologicaly identified lacunosum-moleculare (LM) interneurons of the CA1 region of rat hippocampal slices. The blind whole cell patch-clamp technique was used, and anoxia was induced by superfusion of the slice with an anoxic artificial cerebral spinal fluid saturated with 95% N2-5% CO2 for 4-6 min. 2. In LM interneurons, anoxia generated currents similar to those in pyramidal cells, the most prominent being anoxic and postanoxic outward currents. The adenosine A1 type receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 200 nM) did not significantly affect anoxia-generated currents. 3. EPSCs and polysynaptic IPSCs (pIPSCs) evoked in LM interneurons by "distant" stimulation (> 1 mm) in the stratum radiatum were strongly depressed by anoxia and recovered upon reoxygenation. 4. Responses to pressure application of glutamate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and N-methyl-D-aspartate (NMDA) were not significantly affected by anoxia, suggesting that the suppression of EPSCs is due to presynaptic mechanisms. 5. DPCPX (200 nM) prevented anoxia-induced suppression of EPSCs, suggesting that this suppression was mediated by presynaptic A1 adenosine receptors. 6. Monosynaptic IPSCs evoked by "close" stimulation (< 0.5 mm) in the stratum radiatum, in the presence of glutamate-receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 20 microM) and D-2-amino-5-phosphopentanoate (APV; 50 microM), were reversibly depressed but not blocked by anoxia. 7. Anoxia depressed monosynaptic GABAA receptor-mediated IPSCs (monosynaptic IPSCAs) by inducing a positive shift in the reversal potential and a decrease in slope conductance. Responses to pressure-applied isoguvacine, a GABAA receptor agonist, were reversibly depressed by anoxia, again because of a positive shift in reversal potential and decrease in conductance. Anoxic effects on slope conductances and reversal potential of isoguvacine responses and monosynaptic IPSCA coincided, suggesting that evoked transmitter release from GABAergic terminals was not affected by anoxia. 8. Anoxic depression of monosynaptic GABAB receptor-mediated IPSCs (monosynaptic IPSCBs) was due to a decrease in the slope conductance of monosynaptic IPSCB. In contrast to EPSCs, DPCPX (200 nM) failed to prevent anoxia-induced depression of mIPSCA and mIPSCB. 9. Paired-pulse depression of monosynaptic IPSCs, partially mediated by presynaptic GABAB receptors, was not affected by anoxia. 10. These data provide direct evidence for the hypothesis that inhibitory interneurons of CA1 stratum LM are functionally disconnected from excitatory inputs by anoxia. This disconnection underlies the preferential block by anoxia of IPSCs recorded in pyramidal cells, and it may occult the postsynaptic modifications in GABAA and GABAB responses. This disconnection involves adenosine-dependent inhibition of glutamate release from excitatory terminals. GABA release and its modulation by presynaptic GABAB receptors, both known to be insensitive to adenosine, seems to be resistant to anoxia.

Gabapentin Increases a Tonic Inhibitory Conductance in Hippocampal Pyramidal Neurons

2006 ◽  
Vol 105 (2) ◽  
pp. 325-333 ◽  
Author(s):  
Victor Y. Cheng ◽  
Robert P. Bonin ◽  
Mary W. Chiu ◽  
J Glen Newell ◽  
John F. MacDonald ◽  
...  
Keyword(s):  
Gabaa Receptors ◽  
Hippocampal Neurons ◽  
Gabab Receptors ◽  
Gamma Aminobutyric Acid ◽  
Western Blots ◽  
Inhibitory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Inhibitory Conductance ◽  
Tonic Current

Background The mechanisms underlying the therapeutic actions of gabapentin remain poorly understood. The chemical structure and behavioral properties of gabapentin strongly suggest actions on inhibitory neurotransmission mediated by gamma-aminobutyric acid (GABA); however, gabapentin does not directly modulate GABAA or GABAB receptors. Two distinct forms of GABAergic inhibition occur in the brain: postsynaptic conductance and a persistent tonic inhibitory conductance primarily generated by extrasynaptic GABAA receptors. The aim of this study was to determine whether gabapentin increased the tonic conductance in hippocampal neurons in vitro. As a positive control, the effects of vigabatrin, which irreversibly inhibits GABA transaminase, were also examined. Methods GABAA receptors in hippocampal neurons from embryonic mice were studied using whole cell patch clamp recordings. Miniature inhibitory postsynaptic currents and the tonic current were recorded from cultured neurons that were treated for 36-48 h with gabapentin, vigabatrin, or gabapentin and vigabatrin. To determine whether gabapentin increased the expression of GABAA receptors, Western blots were stained with antibodies selective for alpha1, alpha2, and alpha5 subunits. Results GABAA receptors were insensitive to the acute application of gabapentin, whereas chronic treatment increased the amplitude of the tonic current threefold (EC50 = 209 microm) but did not influence miniature inhibitory postsynaptic currents. Vigabatrin increased the tonic conductance, and the maximally effective concentration did not occlude the actions of gabapentin, which suggests that these compounds act by different mechanisms. Neither gabapentin nor vigabatrin increased the expression of GABAA receptors in the neurons. Conclusions Gabapentin increases a tonic inhibitory conductance in mammalian neurons. High-affinity GABAA receptors that generate the tonic conductance may detect small increases in the ambient concentration of neurotransmitter caused by gabapentin.

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