Perpetual inhibitory activity in mammalian brain slices generated by spontaneous GABA release (original) (raw)
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The Journal of Physiology, 1989
The mechanisms involved in the lability of inhibition at higher frequencies of stimulation were investigated in the guinea-pig in vitro neocortical slice preparation by intracellular recording techniques. We attempted to test the possibility of a feedback depression of GABA on subsequent release. 2. At resting membrane potential (Em,-75-8 + 5-2 mV) stimulation of either the pial surface or subcortical white matter evoked a sequence of depolarizing and hyperpolarizing synaptic components in most neurones. An early hyperpolarizing component (IPSPA) was usually only obvious as a pronounced termination of the EPSP. followed by a later hyperpolarizing event (IPSPB). Current-voltage relationships revealed two different conductances of about 200 and 20 nS and reversal potentials of-73-0+444 and-88-6+6 1 mV for the early and late component. respectively. 3. The conductances of IPSPA and IPSPB were fairly stable at a stimulus frequency of 0-1 Hz. At frequencies between 0-5 and 2 Hz both IPSPs were attenuated with the second stimulus and after about five stimuli a steady state was reached. Concomitantly IPSPs were shortened. The average decrease in synaptic conductance between 0-1 and 1 Hz was 80% for the IPSPA and 60% for the IPSPB. At these frequencies the reversal potentials decreased by 5 and 2 mV, respectively; Em and input resistance (Rin) were not consistently affected. 4. The amplitudes of field potentials, action potentials and EPSPs of pyramidal cells were attenuated less than 10% at stimulus frequencies up to 1 Hz, suggesting that alterations in local circuits between the stimulation site and excitatory input onto inhibitory interneurones may play only a minor role in the frequency-dependent decav of IPSPs. 5. Localized application of GABA produced multiphasic responses. With low concentrations and application near the soma an early hyperpolarization prevailed followed by a depolarizing late component. Brief application of GABA at low frequencies induced constant responses; at higher frequencies, the responses sometimes declined. The current-voltage relationships of the two GABA responses
The Journal of Physiology, 1991
Intracellular recording techniques were used to study synaptic potentials in CA3 pyramidal cells elicited with mossy fibre stimulation in partially disinhibited hippocampal slice cultures. Two experimental protocols were used: (1) high concentrations (20-40 gM) of the A-type y-aminobutyric acid (GABAA) receptor antagonist bicuculline plus low concentrations (2-4 /sM) of the glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), or (2) low concentrations (1-2 5 ,lM) of bicuculline alone. 2. Under the first condition, stimulation of mossy fibre afferents evoked epileptic bursts alternating with a response consisting of an excitatory postsynaptic potential (EPSP) followed by an unusually large and long-lasting hyperpolarizing potential with a maximal amplitude in the range of-30 mV from the resting membrane potential. 3. This paroxysmal inhibitory potential (PIP) had a reversal potential near that of potassium. The amplitude of the PIP was not dependent on action potentials superimposed on the preceding EPSP, and was present in cells recorded with microelectrodes containing the Ca2" chelator EGTA. These data suggest that the PIP is not a Ca2"-activated K+ potential. 4. The PIP was prolonged by the GABA-uptake blocker nipecotic acid, was reduced by hyperpolarizing interneurons with the opioid agonist FK 33-824, and was abolished by the GABAB-receptor antagonist CGP 35 348. These data indicate that the PIP is mediated by the activation of GABAB receptors following GABA release from interneurons. 5. The NMDA-receptor antagonist D-2-amino-5-phosphonovalerate (D-APV) strongly reduced the amplitude of the PIP, but had no effect on the GABAB receptor-mediated inhibitory postsynaptic potential (IPSP) under control conditions. 6. Under the first condition, regular stimulation elicited a cyclical pattern of evoked responses. There was either an alternation between an epileptic burst and a PIP or, at shorter interstimulus intervals, a sequence of gradually increasing PIPs followed by an epileptic burst, which then reset the cycle. MS 9234 376 M. SCANZIANI, B. H. GAHWILER AND S. M. THOMPSON 7. Under the second condition, in low concentrations of bicuculline alone, the early GABAA-mediated IPSP was little affected, but the late GABAB-mediated IPSP was greatly enhanced. These enhanced late IPSPs were comparable in amplitude and duration to the PIPs seen under the first conditions, could exhibit cyclical behaviour, and were reduced by D-APV. 8. Application of CGP 35 348 abolished the late IPSP under control conditions, but had no effect on hippocampal excitability. In contrast, CGP 35 348 blocked the PIP elicited in low bicuculline, and consequently led to intense epileptic discharge. 9. We suggest that the amplification of GABAB receptor-mediated synaptic potentials after partial disinhibition may be an important endogenous compensatory mechanism preventing epileptogenesis.
1997
Rapid applications of GABA (from 10 M to 10 mM) to outsideout patches were used to study the role that the kinetic properties of GABA A receptors play in determining the time course of IPSCs in neocortical pyramidal neurons. Currents induced by rapid applications of brief (1 msec) pulses of GABA (1 mM) showed a biexponential decay phase that seems to involve the entry of GABA A receptors into desensitized states. This conclusion is based on the similar fast decay kinetics of the response to brief and prolonged pulses of GABA and on the correlation between the degree of paired-pulse depression and the decay rate of the currents induced by brief pulses.
Synapse, 1992
Following micropressure application of glutamate (500 p M ) in stratum lacunosum-moleculare (L-MI, inhibitory postsynaptic potentials (glut-IPSPs) were recorded in CA1 pyramidal cells. These glut-IPSPs were blocked by tetrodotoxin (1 pM) and, thus, were probably generated by the activation of local interneurons. The effects of pharmacological antagonists on glut-IPSPs and on electrically-evoked early and late IPSPs were assessed in the same cells during the same application of the antagonist. Local application of the GABA, antagonist 2-OH saclofen (1-4 mM) reduced both glut-IPSPs and late IPSPs but not early IPSPs. In contrast, the GABAB antagonist phaclofen (20 mM) reduced late IPSPs but not early IPSPs or glut-IPSPs. Barium (1 mM), a blocker of some K' channels, diminished late IPSPs but not early IPSPs or glut-IPSPs. Early IPSPs were blocked by the GABAA antagonists bicuculline and picrotoxin but late IPSPs and glut-IPSPs were not. Repetitive electrical stimulation depressed early and late IPSPs as well as glut-IPSPs, suggesting that interneurons activated with glutamate were also stimulated electrically. Thus, interneurons in str. lacunosum-moleculare appear to inhibit pyramidal cells via a GABAB receptor-mediated IPSP. The discrepancy in the pharmacological profile of the GABAB glut-IPSPs and of the GABAB late IPSPs may suggest the presence of two GABAB mechanisms in CA1 pyramidal cells. 0 1992 Wiley-Liss, Inc.
Neuropharmacology, 2001
High-frequency stimulation of afferents to the supraoptic nucleus (SON) results in a robust increase in the frequency and amplitude of pharmacologically isolated, tetrodotoxin-resistant, miniature excitatory postsynaptic currents (mEPSCs) lasting for 5-20 min. This increase in mEPSC frequency, termed short-term potentiation (STP), is tightly coupled to increases in action potential firing in magnocellular neurons (MCNs) suggesting a functional role for STP. gamma-Aminobutyric acid (GABA), acting selectively on GABA(B) receptors, has been shown to modulate action potential-dependent EPSCs, as well as mEPSCs in this nucleus. In this study, we examined the role of GABA in STP. Using in vitro hypothalamic slices containing the SON and the nystatin perforated-patch recording technique to record from MCNs, we tested the hypothesis that GABA modulates STP. Baclofen, a GABA(B) receptor agonist, caused a reversible decrease in the frequency of mEPSCs as well as a reduction in the magnitude and duration of STP. GABA(B) receptor antagonists blocked the baclofen-induced decrease in mEPSC frequency and reduction in STP. In addition, the antagonists by themselves increased basal mEPSC frequency while prolonging the duration of STP in most cells. By contrast, picrotoxin, a GABA(A) chloride channel blocker, had no effect on STP.These findings indicate that GABA is tonically present in the SON and its action at the GABA(B) receptor may determine the magnitude and duration of STP.
The Journal of Physiology, 1997
1. Tight-seal, whole-cell recording was used to study GABAB receptor-mediated inhibition of spontaneous inhibitory synaptic currents in cultured rat midbrain neurones. 2. Spontaneous miniature inhibitory postsynaptic currents (mIPSCs) were recorded in tetrodotoxin (ITX), Cd2+ and Ba2+. (R)-(-)-baclofen reduced the frequency of mIPSCs through a presynaptic mechanism. The EC50 for this effect was 7 4zM. It was antagonized by the GABAB receptor antagonist CGP55845A (05 /uM). 3. In pertussis toxin (PTX)-treated cultures, some GABAB receptor-mediated reduction of the frequency of mIPSCs persisted. In contrast, PTX treatment totally abolished inhibition of miniature excitatory postsynaptic currents (mEPSCs).
Cerebral cortex (New York, N.Y. : 1991), 2014
Idiopathic epilepsies have frequently been linked to mutations in voltage-gated channels (channelopathies); recently, mutations in several genes encoding presynaptic proteins have been shown to cause epilepsy in humans and mice, indicating that epilepsy can also be considered a synaptopathy. However, the functional mechanisms by which presynaptic dysfunctions lead to hyperexcitability and seizures are not well understood. We show that deletion of synapsin II (Syn II), a presynaptic protein contributing to epilepsy predisposition in humans, leads to a loss of tonic inhibition in mouse hippocampal slices due to a dramatic decrease in presynaptic asynchronous GABA release. We also show that the asynchronous GABA release reduces postsynaptic cell firing, and the parallel impairment of asynchronous GABA release and tonic inhibition results in an increased excitability at both single-neuron and network levels. Restoring tonic inhibition with THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin...
The Journal of physiology, 1993
1. Tight-seal, whole-cell voltage clamp recording techniques were used to characterize monosynaptically evoked GABAB currents in adult rat brain slices maintained at 34-35 degrees C. Responses were recorded from granule cells of the dentate gyrus following the blockade of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)-, D-2-amino-5-phosphonovaleric acid (D-AP5)- and picrotoxin-sensitive fast synaptic transmission, so that the remaining synaptic currents could be studied in isolation. 2. Under these conditions, stimulation in the molecular layer elicited a slow outward current which was blocked by the selective GABAB antagonist CGP 35348 in a concentration-dependent manner (200-800 microM). This current was absent in recordings made with pipettes containing 10-15 mM of the lidocaine derivative QX-314 or when caesium was substituted for K+. 3. Increasing the [K+]o e-fold (from 2.5 to 6.8 mM) shifted the reversal potential of the GABAB current from -97.9 to -73.2 mV, as predicted by the N...
GABAB receptor-mediated effects in human and rat neocortical neurones in vitro
Neuropharmacology, 1999
GABA B receptor-mediated responses were investigated in human and rat neocortical neurones in vitro by using intracellular recording. Human epileptogenic tissue and cortex from rats were compared for differences related to the cellular mechanisms of hyperexcitability. In both tissues, single stimuli of various intensities were used to compare basic properties of excitatory and inhibitory postsynaptic potentials (EPSP, IPSP). Paired stimuli, causing a decrease of a second IPSP, were used as an index of presynaptic activation of GABA B receptors. In neocortical neurones of rats, increasing intensities of stimulation elicited at low intensities (6-8 V) a fairly pure EPSP which was curtailed at higher stimulus intensities (10-14 V) by a GABA A receptor mediated IPSP (IPSP A). In all rat neocortical neurones the IPSP A was followed by a late inhibitory component (IPSP B , time to peak about 150 ms) which was eliminated by the GABA B receptor antagonists CGP 35348 or CGP 55845A. On average, paired stimuli reduced the amplitude of a second IPSP A to 57% of the first (in the presence of 10 mM CNQX and 20 mM D-APV). Paired-pulse depression was only antagonized by CGP 55845A, but not by CGP 35348. The magnitude and time course of paired-pulse depression was markedly enhanced at lower temperatures. In human cortical neurones obtained following epilepsy surgery only low intensity stimuli (4 V) elicited EPSPs. Intermediate to higher stimulus intensities (8-10 V) elicited often all-or-none depolarization shifts or prolonged and increased EPSPs. Few neurones exhibited a sequence of EPSP and IPSPs comparable to that observed in rat neurones. Application of CGP 55845A caused little change in excitability near 150 ms, indicating that the IPSP B is weak. Paired-pulse depression of inhibition was small in most neurones, the second IPSPA was reduced to 82.8% of the first at a 500 ms interval (n=6). Only two neurones exhibited a paired-pulse depression comparable to rat neurones. The consequences of GABA receptor-mediated paired-pulse depression on neuronal synchronisation are discussed towards the different cellular mechanisms of focal and bilateral synchronous epilepsies.