Factors Contributing to the Decay of the Stimulus-Evoked IPSC In Rat Hippocampal CA1 Neurons (original) (raw)
Related papers
Naunyn-Schmiedeberg's Archives of Pharmacology, 1994
The synaptic release of ?-aminobutyric acid (GABA) is thought to be regulated by presynaptic GABA receptors of the B-type. It was the goal of this study to validate this concept electrophysiologically using four selective antagonists of GABA-B receptors. Experiments were performed in hippocampal slices exposed to 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX 30gM) and D-2-amino-5-phosphonopentanoate (AP5 40 gM) in order to block excitatory transmission. Consequently, electrical stimulation of the Schaffer collateral/commissural fibers evoked monosynaptic inhibitory potentials (IPSP) recorded intracellularly from CA 1 pyramidal neurons. In a test called paired-pulse paradigm two identical stimuli were applied at intervals ranging from 350 to 4000 ms. The IPSP evoked by the second stimulation was smaller in its amplitude over the entire interval range. This reduction of the second GABA-response is thought to result from the activation of presynaptic GABA receptors. The GABA-uptake inhibitor SKF 89976 (100 gM) increased the amplitude of the IPSP's and increased the ratio of the first to the second IPSP amplitude. These findings indicate that the drug increases the GABA content in the synaptic cleft leading to a facilitation of paired-pulse depression. The actions of four bath-applied GABA-B receptor antagonists were examined in the paired-pulse paradigm. None of these compounds abolished paired-pulse inhibition completely even at concentrations higher than those required to block postsynaptic GABA-B responses. The potent GABA-B antagonists CGP 55845 and CGP 52432 reduced paired-pulse depression by 80% at 10 gM (maximal effect). The other two compounds, CGP 46381 and CGP 36742 had no significant or only a subtle effect respectively. The adenosine receptor antagonist, caffeine (100 gM) and the metabotropic excitatory amino acid receptor antagonist (1S, 3 R)-l-aminocyclopentane-1,3-dicarboxylic Correspondence to: H.-R. Olpe at the above address acid (MCPG, 1 raM)) had no effect on paired-pulse depression in the presence of CGP 55845 (10 ~tM). In conclusion since all CGP compounds are GABA-B antagonists at postsynaptic sites these findings suggest that there may be differences between the pre-and postsynaptic GABA-B receptors. Apart from presynaptic GABA-B receptors there appear to exist additional mechanisms involved in paired-pulse depression that remain to be elucidated.
British Journal of Pharmacology, 1999
Synaptic activation of g-aminobutyric acid (GABA) B receptors at GABA synapses causes (a) postsynaptic hyperpolarization mediating a slow inhibitory postsynaptic potential/current (IPSP/C) and (b) presynaptic inhibition of GABA release which depresses IPSPs and leads to paired-pulse widening of excitatory postsynaptic potentials (EPSPs). To address whether these eects are mediated by pharmacologically identical receptors the eects of six GABA B receptor antagonists of widely ranging potencies were tested against each response. 2 Monosynaptic IPSP B s were recorded in the presence of GABA A , AMPA/kainate and NMDA receptor antagonists. All GABA B receptor antagonists tested depressed the IPSP B with an IC 50 based rank order of potency of CGP556795CGP56433=CGP55845A=CGP524324CGP511764 CGP36742. 3 Paired-pulse EPSP widening was recorded as an index of paired-pulse depression of GABAmediated IPSP/Cs. A similar rank order of potency of antagonism of paired-pulse widening was observed to that for IPSP B inhibition. 4 Comparison of the IC 50 values for IPSP B inhibition and paired-pulse EPSP widening revealed a close correlation between the two eects in that their IC 50 s lay within the 95% con®dence limits of a correlation line that described IC 50 values for inhibition of paired-pulse EPSP widening that were 7.3 times higher than those for IPSP B inhibition. 5 Using the compounds tested here it is not possible to assign dierent subtypes of GABA B receptor to pre-and post-synaptic loci at GABAergic synapses. However, 5 ± 10 fold higher concentrations of antagonist are required to block presynaptic as opposed to postsynaptic receptors when these are activated by synaptically released GABA.
Presynaptic kainate receptors that enhance the release of GABA on CA1 hippocampal interneurons
Neuron, 2001
on presynaptic GABAergic terminals in the cerebellum, and their activation leads to an increase (Bureau and 13273 Marseille France Mulle, 1998; Glitsch and Marty, 1999) or a decrease (Satake et al., 2000) of GABA release. † Division of Neuroscience S700 The purpose of this study was to investigate whether GABA quantal release is modulated by presynaptic glu-Baylor College of Medicine Houston, Texas 77030 tamate receptors at various classes of interneuroninterneuron synapses in the hippocampus. Attention was focused on kainate because these receptors are widely expressed in most classes of interneurons (Bahn Summary et al., 1994; Petralia et al., 1994; Siegel et al., 1995), raising the possibility of their expression in presynaptic We report that kainate receptors are present on presynaptic GABAergic terminals contacting interneu-GABAergic terminals, and because kainate receptors are hypothesized to play an important role as modula-rons and that their activation increases GABA release. Application of kainate increased the frequency of min-tors of GABAergic activity (Fisher and Alger, 1984; Cossart et al., 1998; Rodriguez-Moreno et al., 1997; Bureau iature inhibitory postsynaptic currents recorded in CA1 interneurons. Local applications of glutamate but not of et al., 1999; Frerking et al., 1999). We report that kainate receptors are present on AMPA or NMDA also increased GABA quantal release. Application of kainate as well as synaptically released GABAergic terminals contacting various classes of morphologically identified CA1 interneurons. Bath applica-glutamate reduced the number of failures of GABAergic neurotransmission between interneurons. Thus, acti-tion of kainate or glutamate but not of any other agonist for ionotropic or metabotropic glutamate receptors in-vation of presynaptic kainate receptors increases the probability of GABA release at interneuron-interneuron creased the frequency of miniature inhibitory postsynaptic currents (mIPSCs) on interneurons without affect-synapses. Glutamate may selectively control the communication between interneurons by increasing their ing their amplitude. We also show that bath-applied kainate or synaptically released glutamate selectively mutual inhibition. decreased the failure rate of evoked GABAergic responses on CA1 interneurons. Therefore, the activation Introduction of presynaptic kainate receptors increases the efficacy of GABAergic transmission between interneurons. Inhibitory GABAergic interneurons play a crucial role in shaping cortical activity (Cobb et al., 1995; Buzsaki, 1997; Tamas et al., 2000). They are densely intercon-Results nected via chemical (GABAergic) and electrical synapses, and this interconnectivity is believed to enhance Since presynaptic receptors can differently regulate acthe computational power of cortical networks (Galarreta tion potential-dependent and-independent release of and Hestrin, 1999; Gibson et al., 1999; Fukuda and Koneurotransmitter (Glitsch and Marty, 1999), two types saka, 2000). In that respect, the regulation of presynaptic of experiments are available to assess the presence GABAergic terminals is crucial to consider, since an upof presynaptic receptors: (1) the recording of miniature or downregulation of GABA release can modify neuronal events, a change in their frequency but not of their amplinetwork function/behavior, as occurs in synaptic plastude, indicating a presynaptic effect, and (2) assessing ticity (Wigstrom and Gustafsson, 1983), oscillations the probability of failure of synaptic transmission evoked (Hajos et al., 2000), or epilepsy (Prince and Jacobs, 1998; by the electrical activation of a presynaptic axon. Both Hirsch et al., 1999). approaches were used in this study. Transmitter release at presynaptic GABAergic terminals can be regulated by a variety of neuromodulators and Low Concentrations of Kainate Increase neurotransmitters including GABA itself and the ubiquithe Frequency of Miniature GABAergic tous excitatory neurotransmitter glutamate (MacDermott Currents in CA1 Interneurons et al., 1999). The control of GABA release by glutamate To determine whether kainate modulates miniature receptors is best documented for metabotropic recep-GABAergic currents at GABAergic synapses on intertors. The activation of presynaptic glutamatergic metaneurons, we have recorded mIPSCs (Vhold, ϩ 10mV) from botropic receptors at GABAergic terminals generally 37 visually identified interneurons of stratum radiatum and stratum oriens in the CA1 region of the hippocampus. In all experiments, we used a low concentration ‡ To whom correspondence should be addressed (e-mail: ben-ari@ inmed.univ-mrs.fr). of kainate (250 nM) that selectively activates kainate brought to you by CORE View metadata, citation and similar papers at core.ac.uk
Neuroscience, 1999
Use-dependent depression of inhibitory postsynaptic potentials was investigated with intracellular recordings and the paired-pulse paradigm in rat neocortical neurons in vitro. Pairs of stimuli invariably reduced the second inhibitory postsynaptic potential-A (GABA A receptor-mediated inhibitory postsynaptic potential) of a pair; at interstimulus intervals of 500 ms, the amplitude of the second inhibitory postsynaptic potential-A was considerably smaller than the first (36.2^6.2%, n17). Decreasing the interstimulus interval reduced the second inhibitory postsynaptic potential-A further and with interstimulus intervals shorter than 330 ms the compound excitatory postsynaptic potential-inhibitory postsynaptic potential response reversed from a hyperpolarizing to a depolarizing response. The depression of the inhibitory postsynaptic potential-A exhibited a maximum at interstimulus intervals near 150 ms and recovered with a time constant of 282^96.2 ms. Elimination of excitatory transmission by the application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and d(Ϫ)-2-amino-5-phosphonovaleric acid yielded an essentially unaltered time-course of paired-pulse depression (maximum depression near 150 ms, time constant of recovery 232^98 ms). The polarity change of the compound excitatory postsynaptic potential response at shorter interstimulus intervals was abolished in the presence of CNQX and d(Ϫ)-2-amino-5-phosphonovaleric acid. CNQX and d(Ϫ)-2-amino-5-phosphonovaleric acid also reduced the apparent depolarizing shift of the reversal potential between the first and second inhibitory postsynaptic potential-A from about 6 mV to less than 2 mV. Application of the GABA B receptor antagonist CGP 55845A in the presence of CNQX and d(Ϫ)-2-amino-5-phosphonovaleric acid abolished the inhibitory postsynaptic potential-B and paired-pulse depression. Under these conditions, the amplitude of the second inhibitory postsynaptic potential was, on average, about 90% of the first, i.e. reduced by about 10%. The second inhibitory postsynaptic potential-A was approximately constant at interstimulus intervals between 100 and 500 ms. It is concluded that paired-pulse depression of cortical inhibition is predominantly mediated by presynaptic GABA B receptors of GABAergic interneurons. The abolition of net inhibition at interstimulus intervals near 330 ms may facilitate spread of excitation and neuronal synchrony during repetitive cortical activation near 3 Hz. This use-dependent depression of inhibition may contribute to highly synchronized slow electroencephalogram activity during spike-and-wave or delta activity.
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
British Journal of Pharmacology, 1999
Synaptic activation of g-aminobutyric acid (GABA) B receptors at GABA synapses causes (a) postsynaptic hyperpolarization mediating a slow inhibitory postsynaptic potential/current (IPSP/C) and (b) presynaptic inhibition of GABA release which depresses IPSPs and leads to paired-pulse widening of excitatory postsynaptic potentials (EPSPs). To address whether these eects are mediated by pharmacologically identical receptors the eects of six GABA B receptor antagonists of widely ranging potencies were tested against each response. 2 Monosynaptic IPSP B s were recorded in the presence of GABA A , AMPA/kainate and NMDA receptor antagonists. All GABA B receptor antagonists tested depressed the IPSP B with an IC 50 based rank order of potency of CGP556795CGP56433=CGP55845A=CGP524324CGP511764 CGP36742. 3 Paired-pulse EPSP widening was recorded as an index of paired-pulse depression of GABAmediated IPSP/Cs. A similar rank order of potency of antagonism of paired-pulse widening was observed to that for IPSP B inhibition. 4 Comparison of the IC 50 values for IPSP B inhibition and paired-pulse EPSP widening revealed a close correlation between the two eects in that their IC 50 s lay within the 95% con®dence limits of a correlation line that described IC 50 values for inhibition of paired-pulse EPSP widening that were 7.3 times higher than those for IPSP B inhibition. 5 Using the compounds tested here it is not possible to assign dierent subtypes of GABA B receptor to pre-and post-synaptic loci at GABAergic synapses. However, 5 ± 10 fold higher concentrations of antagonist are required to block presynaptic as opposed to postsynaptic receptors when these are activated by synaptically released GABA.
Saturation and self-inhibition of rat hippocampal GABAA receptors at high GABA concentrations
European Journal of Neuroscience, 2002
Current responses to ultrafast g-aminobutyric acid (GABA) applications were recorded from excised patches in rat hippocampal neurons to study the gating properties of GABA A receptors at GABA concentrations close to saturating ones and higher. The amplitude of currents saturated at approximately 1 mM, while the onset rate of responses reached saturation at 4±6 mM GABA. At high GABA concentrations (> 10 mM), the amplitude of current responses was reduced in a dose-dependent manner with a half-blocking GABA concentration of approximately 50 mM. The peak reduction at high GABA doses was accompanied by a tendency to increase the steady-state to peak ratio. At concentrations higher than 30 mM, this effect took the form of a rebound current, i.e. during the prolonged GABA applications, the current ®rstly declined due to desensitization onset and then, instead of decreasing towards a steady-state value, clearly increased. Both the self-inhibition of GABA A receptors by high GABA doses and rebound were clearly voltage dependent, being larger at positive holding potentials. The fast desensitization component accelerated with depolarization at all saturating [GABA] tested. The rebound phenomenon indicates that the self-block of GABA A receptors is state dependent, and suggests that the sojourn in the desensitized conformation provides a`rescue' from the block. We propose that high GABA concentrations inhibit the receptors by direct occlusion of the channel pore having no effect on the receptor gating.
Perpetual inhibitory activity in mammalian brain slices generated by spontaneous GABA release
Brain Research, 1991
Miniature spontaneous inhibitory postsynaptic currents (slPSCs) mediated by GABA A receptors were recorded using whole-cell patch clamp recordings in rat brain slices maintained in vitro at 34 _+ 1 °C. We have found that firing of action potentials by principal neurons or by GABAergic interneurons is not necessary to the generation of sIPSCs since they persist in the presence of 1-5/tM tetrodotoxin (TrX). The average frequency of the discrete sIPSCs exhibits a large cell-to-cell variability and is between 5-15 Hz. The amplitudes of the sIPSCs depend on the difference between the membrane potential and the equilibrium potential for Cl-(Eo). Generally, 70-80 mV away from E a, sIPSCs have a mean amplitude of 30-80 pA (i.e. peak conductance of 400-1000 pS) with an average decay time constant of 5.8 ms. Accordingly, unitary single sIPSCs arise from the simultaneous activation of no more than 20 GABA A receptor/channels. The perpetual barrage of spontaneous GABAergic activity is very likely to be a critical factor in the regulation of neuronal excitability and the mechanism of action of several neuroactive compounds.