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PubMed2004

Blockade of presynaptic adenosine A1 receptor responses by nitric oxide and superoxide in rat hippocampus.

Activation of N-methyl-D-aspartate (NMDA) receptors prevents the neuronal responses to adenosine in hippocampal slices. As NMDA receptor activation leads to the generation of nitric oxide (NO) and superoxide, we have examined whether these can modify neuronal responses to adenosine and mediate the actions of NMDA. Field excitatory postsynaptic potentials were recorded in the CA1 region of rat hippocampal slices. Paired-pulse interactions were studied to localize the observed interactions to presynaptic terminals. The NO donors S-nitroso-N-acetylpenicillamine and diethylamine NONOate induced a long-lasting potentiation (NO-induced potentiation) of field excitatory postsynaptic potential slope and significantly prevented the presynaptic inhibitory effect of adenosine or the A1 receptor agonist N6-cyclopentyladenosine selectively with no effect on responses to baclofen. The superoxide-generating system of xanthine/xanthine oxidase also prevented presynaptic responses to adenosine and this effect was prevented by superoxide dismutase (SOD). The guanylate cyclase inhibitor 1H-[1,2,4]-oxadiazolo[4,3a]quinoxalin-1-one (10 microM) prevented NO-induced potentiation and the inhibitory effects of S-nitroso-N-acetylpenicillamine and xanthine/xanthine oxidase on adenosine responses. The inhibitory effect of NMDA on adenosine responses was unchanged by 1H-[1,2,4]-oxadiazolo[4,3a]quinoxalin-1-one, indicating that guanosine-3',5-cyclic monophosphate does not mediate this interaction, although it was partially reduced by SOD, suggesting that superoxide might contribute. The reduction of adenosine responses by electrically-induced long-term potentiation was prevented by NO synthase inhibition or SOD. The results indicate that the presynaptic effects of adenosine at presynaptic sites can be prevented by NO or superoxide but that neither of these individually can fully account for the prevention of adenosine responses by NMDA.

2-Amino-5-phosphonovalerate↗

PubMed1998

Enhanced bursts of IPSCs in dentate granule cells in mice with regionally inhibited long-term potentiation.

Until recently, most studies on the synaptic-cellular basis of learning and memory concentrated on the activity-dependent changes occurring in principal cells such as hippocampal pyramidal cells and dentate granule cells. However, the ability of the inhibitory interneurons to regulate synaptic plasticity remains less understood. This study tested the hypothesis that the gamma-aminobutyric-acid (GABA)-mediated inhibitory neurotransmission is enhanced in mice that show no detectable long-term potentiation in the dentate gyrus in the absence of the GABAA receptor antagonist bicuculline. Patch clamp recordings were made from dentate granule cells in brain slices from wild-type and Thy-1 knockout (KO) mice. The frequency, amplitude and kinetics of miniature inhibitory postsynaptic currents (mIPSCs, generated by the action potential-independent release of GABA) was not different between animals. However, bursts of spontaneous IPSCs (sIPSCs, generated by both action potential-independent and -dependent GABA release) in KO mice were associated with larger synaptic charge transfers and increased durations. When pairs of IPSCs were evoked at varying intervals, the amplitude of the second response with respect to the first was significantly larger in KO animals. These results further support the concept that enhancement of interneuronal functions in cortical structures can have profound effects on the activity-dependent synaptic plasticity observed in principal cells.

Animals↗

PubMed1993

Nicotinamide adenine dinucleotides mimic adenosine inhibition on synaptic transmission by decreasing glutamate release in rat hippocampal slices.

To assess the possible inhibitory action of nicotinamide adenine dinucleotides on the synaptic release of glutamate, electrophysiological and biochemical experiments were performed on rat hippocampal slices. Perfusion of adenosine, beta-nicotinamide adenine dinucleotide (NAD) or beta-nicotinamide adenine dinucleotide phosphate (NADP), reversibly inhibited the field excitatory postsynaptic potentials (fEPSP). Dose-response curves for their inhibitory action showed that these three substances had a similar potency in the range of concentrations from 0.1 microM to 100 microM. NADP and adenosine (100 microM) halved the K(+)-induced release of endogenous glutamate and aspartate, leaving gamma-amino-butyric acid (GABA) levels unchanged. 3-Isobutyl-1-methylxanthine (IBMX) 200 microM, an antagonist of the P1-purinoreceptors, antagonized the depressant effects of these coenzymes on both fEPSP and also on amino acid release. Based on these results we propose that nicotinamide adenine dinucleotides, similar to adenosine, inhibit excitatory synaptic transmission in the rat hippocampus by decreasing glutamate release from synaptic terminals.

1-Methyl-3-isobutylxanthine↗

PubMedDate not supplied

[A model of the posttetanic efficiency of a neuron dendritic spine].

A model of postsynaptic processes leading to a prolonged posttetanic modification (potentiation and depression) in the efficacy of the excitatory and inhibitory inputs to the neuron CA3 of the hippocampus was developed. The model enables one to estimate changes in postsynaptic potentials depending on the extent of receptor phosphorylation, which is determined by Ca(2+)-dependent changes in secondary messengers.

Animals↗

PubMed1996

GABAB receptors, monoamine receptors, and postsynaptic inositol trisphosphate-induced Ca2+ release are involved in the induction of long-term potentiation at visual cortical inhibitory synapses.

gamma-Aminobutyric acid (GABA)A receptor-mediated inhibitory synaptic transmission in visual cortex undergoes long-term potentiation (LTP), which is input-specific and associative. The present study, conducted under a blockade of ionotropic glutamate receptors, demonstrates an induction mechanism of LTP considerably different from those of associative LTP at excitatory synapses. Inhibitory responses of layer V cells evoked by layer IV stimulation were studied in developing rat visual cortex slices by using intracellular and whole-cell recording methods. LTP induction was prevented by the application of an antagonist for GABAB receptors but not for GABAA or metabotropic glutamate receptors. Inhibition of postsynaptic G-proteins, phospholipase C, inositol trisphosphate (IP3) receptors, or Ca2+ increase prevented the generation of LTP, as did the blockade of GABAB receptors. In rat cerebral cortex, GABAB receptor activation is not known to affect the IP3 level by itself. However, it facilitates IP3 formation induced by the activation of alpha 1 adrenoceptors, which are believed to be located postsynaptically. Accordingly, I examined the involvement of these and other amine receptors, including histamine H1, muscarinic acetylcholine, and serotonin 5-HT2 receptors, all of which are coupled to IP3 formation. Only the blockade of alpha 1 adrenoceptors or serotonin 5-HT2 receptors prevented LTP induction in most, but not all, of the cells. These results suggest that LTP induction requires the activation of postsynaptic GABAB receptors and that its effect is mediated at least partly by facilitation of the monoamine-induced IP3 formation, which then causes Ca2+ release from the internal stores in postsynaptic cells.

Animals↗

PubMed2002

The role of chloride-dependent inhibition and the activity of fast-spiking neurons during cortical spike-wave electrographic seizures.

The conventional view is that the cortical paroxysmal depolarizing shift is a giant excitatory postsynaptic potential enhanced by various intrinsic neuronal currents. Other results point out, however, that synaptic inhibition remains functional in many forms of paroxysmal activities and that intense activation of GABAergic interneurons may accentuate the excitation of target pyramidal cells. To determine the role played by cortical inhibitory neurons in paroxysmal discharges, we used single and dual intracellular recordings from electrophysiologically identified neocortical neurons during spontaneously occurring and electrically induced spike-wave electrographic seizures in vivo. Conventional fast-spiking neurons (presumably local inhibitory interneurons) fired at a very high frequency during paroxysmal depolarizing shifts, which corresponded to the electroencephalogram 'spike' components of spike-wave complexes. The firing of fast-spiking neurons preceded the discharges of neighboring regular-spiking neurons. During electrographic seizures, the reversal potential of the GABA (type A)-mediated potentials in regular-spiking neurons was shifted to positive values by 20-30 mV. Data also show that the prolonged hyperpolarizations during the electroencephalogram 'wave' components of spike-wave electrographic seizures do not contain Cl(-)-dependent inhibitory potentials. Moreover, Cl(-)-dependent mechanisms were reduced or absent during the fast runs that are associated with spike-wave complexes in some paroxysms. We conclude that the strong activity of cortical inhibitory neurons during paroxysmal depolarizing shifts induces Cl(-)-dependent depolarizing postsynaptic potentials in target pyramidal neurons, which facilitate the development of electrographic seizures.

Action Potentials↗

PubMed2002

Synaptic mechanisms regulating the activation of a Ca(2+)-mediated plateau potential in developing relay cells of the LGN.

Using intracellular recordings in an isolated (in vitro) rat brain stem preparation, we examined the synaptic responses of developing relay neurons in the dorsal lateral geniculate nucleus (LGN). In newborn rats, strong stimulation of the optic tract (OT) evoked excitatory postsynaptic potentials (EPSPs) that gave rise to a sustained (300-1,300 ms), slow-decaying (<0.01 mV/s), depolarization (25-40 mV). Riding atop this response was a train of spikes of variable amplitude. We refer to this synaptically evoked event as a plateau potential. Pharmacology experiments indicate the plateau potential was mediated by the activation of high-threshold L-type Ca(2+) channels. Synaptic activation of the plateau potential relied on N-methyl-D-aspartate (NMDA) receptor-mediated activity and the spatial and/or temporal summation of retinally evoked EPSPs. Inhibitory postsynaptic responses (IPSPs) did not prevent the expression of the plateau potential. However, GABA(A) receptor activity modulated the intensity of optic tract stimulation needed to evoke the plateau potential, while GABA(B) receptor activity affected its duration. Expression of the plateau potential was developmentally regulated, showing a much higher incidence at P1-2 (90%) than at P19-20 (1%). This was in part due to the fact that developing relay cells show a greater degree of spatial summation than their mature counterparts, receiving input from as many as 7-12 retinal ganglion cells. Early spontaneous retinal activity is also likely to trigger the plateau potential. Repetitive stimulation of optic tract in a manner that approximated the high-frequency discharge of retinal ganglion cells led to a massive temporal summation of EPSPs and the activation of a sustained depolarization (>1 min) that was blocked by L-type Ca(2+) channel antagonists. These age-related changes in Ca(2+) signaling may contribute to the activity-dependent refinement of retinogeniculate connections.

2-Amino-5-phosphonovalerate↗

PubMed2005

Cholecystokinin inhibits evoked inhibitory postsynaptic currents in the rat nucleus accumbens indirectly through gamma-aminobutyric acid and gamma-aminobutyric acid type B receptors.

We recently reported that cholecystokinin (CCK) excited nucleus accumbens (NAc) cells and depressed excitatory synaptic transmission indirectly through gamma-aminobutyric acid (GABA), acting on presynaptic GABAB receptors (Kombian et al. [2004] J. Physiol. 555:71-84). The present study tested the hypothesis that CCK modulates inhibitory synaptic transmission in the NAc. Using in vitro forebrain slices containing the NAc and whole-cell patch recording, we examined the effects of CCK on evoked inhibitory postsynaptic currents (IPSCs) recorded at a holding potential of -80 mV throughout CCK-8S caused a reversible inward current accompanied by a concentration-dependent decrease in evoked IPSC amplitude. Maximum IPSC depression was approximately 25% at 10 microM, with an estimated EC50 of 0.1 microM. At 1 microM, CCK-8S induced an inward current of 28.3 +/- 4.8 pA (n=6) accompanied by an IPSC depression of -18.8% +/- 1.6% (n=6). This CCK-induced IPSC depression was blocked by pretreatment with proglumide (100 microM; -3.7% +/- 6.9%; n=4) and by LY225910 (100 nM), a selective CCKB receptor antagonist (4.4% +/- 2.6%; n=4). It was not blocked by SCH23390 (10 microM; -23.5% +/- 1.3%; P < 0.05; n=7) or sulpiride (10 microM; -21.8% +/- 5.1%; P <0.05; n=4), dopamine receptor antagonists. By contrast, it was blocked by CGP55845 (1 microM; -0.4% +/- 3.4%; n=5) a potent GABAB receptor antagonist, and by forskolin (50 microM; 9.9% +/- 5.2%; n=4), an adenylyl cyclase activator, and H-89 (1 microM; 6.9% +/- 3.9%; n=4), a protein kinase A (PKA) inhibitor. These results indicate that CCK acts on CCKB receptors to increase extracellular levels of GABA, which then acts on GABAB receptors to decrease IPSC amplitude.

Adenylyl Cyclases↗

PubMed2003

Effects of the GABA-uptake inhibitor tiagabine in rat globus pallidus.

To elucidate the cellular action of tiagabine, an inhibitor of GAT-1 GABA transporter, in the globus pallidus, whole-cell patch-clamp recordings were made from rat globus pallidus neurons in the acutely prepared brain slice. Superfusion of tiagabine significantly prolonged the decay kinetics of both action potential-dependent and -independent (tetrodotoxin-resistant) inhibitory postsynaptic currents (IPSCs) that were mediated by GABA(A) receptors. Furthermore, it decreased the frequency of these IPSCs. The latter effect was reversed by the GABA(B) receptor antagonist CGP55845, which alone had no effect, suggesting the involvement of presynaptic GABA(B) receptors. Thus, tiagabine could inhibit or disinhibit globus pallidus neurons by increasing the activation of the GABA(A) receptors and presynaptic GABA(B) receptors, respectively. In the behaving animal, tiagabine when injected unilaterally into the globus pallidus caused consistent ipsilateral rotation of the rats indicative of increased inhibition of globus pallidus activity. This finding could be explained by the proposition that in the presence of tiagabine, prolonged action of GABA on GABA receptors would dominate over the inhibitory effect of tiagabine on GABA release. Our findings on the electrophysiological and behavioral effects of tiagabine in globus pallidus suggest that this basal ganglia nucleus is one of the sites of action of tiagabine and provides a rationale for investigating its involvement in epilepsy.

Animals↗

PubMed2001

Ryanodine-, IP3- and NAADP-dependent calcium stores control acetylcholine release.

Injections of inositol trisphosphate (IP3) or nicotinamide adenine dinucleotide phosphate (NAADP) into the presynaptic neurone of an identified cholinergic synapse in the buccal ganglion of Aplysia californica increased the amplitude of the inhibitory postsynaptic current evoked by a presynaptic action potential. This suggests that Ca2+ release from various Ca2+ stores can modulate acetylcholine (ACh) release. Specific blockade of the calcium-induced calcium release (CICR) mechanism with ryanodine, or of IP3-induced calcium release with heparin, abolished the effects of IP3, but not the effects of NAADP, suggesting the presence of an intracellular Ca2+ pool independent of those containing ryanodine receptors (RyR) or IP3 receptors. To reinforce electrophysiological observations, intracellular [Ca2+]i changes were measured using the fluorescent dye rhod-2. Injections of cyclic ADP-ribose (an activator of RyR), IP3 or NAADP into the presynaptic neurone induced transient increases in the free intracellular Ca2+ concentration. RyR- and IP3-induced increases were prevented by application of respective selective antagonists but not NAADP-induced increases. Our results show that RyR-dependent, IP3-dependent, and NAADP-dependent Ca2+ stores are present in the same presynaptic terminal but are differently involved in the regulation of the presynaptic Ca2+ concentration that triggers transmitter release.

Acetylcholine↗

PubMed1989

In vivo pertussis toxin treatment attenuates some, but not all, adenosine A1 effects in slices of the rat hippocampus.

In order to examine the involvement of G-proteins in mediating the different effects of adenosine A1-receptor stimulation in rat hippocampus we injected pertussis toxin (PTX) intraventricularly close to the hippocampus and examined its effect in slices 48-60 h later. The in vivo PTX treatment caused a partial (50 +/- 5%) inhibition of the [32P]ADP ribosylation produced by PTX added together with [32P]NAD in vitro. Such PTX treatment eliminated the electrophysiologically determined gamma-amino-n-butyric acid (GABA)B receptor response in the hippocampal CA1 region, but GABAA effects were unaffected. The adenosine (50 microM)-mediated hyperpolarization and decrease in input resistance as well as the adenosine-mediated inhibition of low calcium-induced bursting in pyramidal CA1 neurons were virtually abolished. The same was true for the decrease in [3H]cyclic AMP accumulation that is produced by the adenosine analogue R-N6-phenylisopropyl adenosine (R-PIA) in forskolin-treated hippocampal slices. As far as modulation of transmitter release was concerned, the R-PIA (1 microM)-induced inhibition of release of both [3H]noradrenaline (NA) and [3H]acetylcholine (ACh) evoked by field stimulation in hippocampal slices was affected hardly or not at all by pertussis toxin treatment. The inhibitory effect of adenosine on field excitatory postsynaptic potential (EPSP)s evoked in the CA1 region was unaltered by PTX pretreatment. The present results show that in vivo pertussis toxin treatment can inhibit some but not all A1-adenosine-receptor effects. This strongly suggests that closely similar A1 receptors might be coupled to G-proteins that differ in their sensitivity to PTX treatment.

Acetylcholine↗

PubMed2003

Olivocochlear collaterals evoke excitatory effects in onset neurones of the rat cochlear nucleus.

Axons of medial olivocochlear neurones in the superior olivary complex terminate on the outer hair cells of the cochlea and also give off collaterals that terminate in the cochlear nucleus. Previous work in our laboratory, using extracellular recordings in the cochlear nucleus, has indicated that stimulation of the olivocochlear axons may have an excitatory effect on specific cell populations of the cochlear nucleus, such as onset-choppers, in contrast to the peripheral suppressive action of the same axons. We have investigated whether this excitation is produced by action of the olivocochlear collaterals in the cochlear nucleus or whether it is mediated via the peripheral suppression, by measuring intracellular responses in the rat cochlear nucleus to electrical stimulation of the olivocochlear axons in silence. The results demonstrate that single shocks applied to the olivocochlear axons can evoke excitatory postsynaptic potentials in onset neurones. We observed an inhibitory effect in one chopper only. In the same animals in all other neurones investigated (i.e. three primary-like neurones and eight choppers) the same stimulation was without any effect on cell membrane potential. We conclude that the excitatory effects in onset neurones are not caused by suppression in the auditory peripheral organ, but by activation of olivocochlear collaterals in the cochlear nucleus.

Animals↗

PubMed2002

Electrophysiological properties of interneurons from intraoperative spiking areas of epileptic human temporal neocortex.

We combined visual-assisted whole-cell recordings with Lucifer Yellow labelling to record in vitro from interneuron-like cells from human epileptic neocortical tissue that exhibited spiking activity in situ. Information from intraoperative electrocorticography, which was performed to tailor resection, were used to select those areas that participate in interictal spiking. Whole-cell recordings from slices prepared from these areas showed that both pyramidal and interneuron-like cells were present and retained their main intrinsic firing patterns, i.e. regular spiking and fast spiking, respectively. Moreover, non-pyramidal interneuron-like cells remained innervated by excitatory inputs as both spontaneous and evoked non-NMDA mediated excitatory postsynaptic potentials were recorded. We conclude that putative inhibitory GABAergic cells are present and functional in the human epileptic tissue.

Action Potentials↗

PubMed2006

The pheromone androstenol (5 alpha-androst-16-en-3 alpha-ol) is a neurosteroid positive modulator of GABAA receptors.

Androstenol is a steroidal compound belonging to the group of odorous 16-androstenes, first isolated from boar testes and also found in humans. Androstenol has pheromone-like properties in both animals and humans, but the molecular targets of its pheromonal activity are unknown. Androstenol is structurally similar to endogenous A-ring reduced neurosteroids that act as positive modulators of GABA(A) receptors. Here we show that androstenol has neurosteroid-like activity as a GABA(A) receptor modulator. In whole-cell recordings from cerebellar granule cells, androstenol (but not its 3beta-epimer) caused a concentration-dependent enhancement of GABA-activated currents (EC(50), 0.4 microM in cultures; 1.4 microM in slices) and prolonged the duration of spontaneous and miniature inhibitory postsynaptic currents. Androstenol (0.1-1 microM) also potentiated the amplitude of GABA-activated currents in human embryonic kidney 293 cells transfected with recombinant alpha1beta2gamma2 and alpha2beta2gamma2 GABA(A) receptors and, at high concentrations (10-300 microM), directly activated currents in these cells. Systemic administration of androstenol (30-50 mg/kg) caused anxiolytic-like effects in mice in the open-field test and elevated zero-maze and antidepressant-like effects in the forced swim test (5-10 mg/kg). Androstenol, but not its 3beta-epimer, conferred seizure protection in the 6-Hz electroshock and pentylenetetrazol models (ED(50) values, 21.9 and 48.9 mg/kg, respectively). The various actions of androstenol in the whole-animal models are consistent with its activity as a GABA(A) receptor modulator. GABA(A) receptors could represent a target for androstenol as a pheromone, for which it is well suited because of high volatility and lipophilicity, or as a conventional hormonal neurosteroid.

Androstenols↗

PubMed1979

Synaptic potentials effect the release of transmitter from locust nonspiking interneurons.

An excitatory synaptic potential in a local nonspiking interneuron of a locust is able to effect the release of chemical transmitter. The consequence is that a discrete inhibitory synaptic potential is evoked in an identified postsynaptic motoneuron. These local interactions between interneurons and motoneurons are of behavioral significance in that they ensure the correct operation of a resistance reflex.

Action Potentials↗

PubMed1994

Large amplitude variability of GABAergic IPSCs in melanotropes from Xenopus laevis: evidence that quantal size differs between synapses.

1. We made in situ whole-cell recordings from melanotropes in the intermediate lobe of the pituitary gland of Xenopus laevis. Melanotropes received spontaneous synaptic inputs that had a fast rise time and a much slower decay. These inputs were GABAergic inhibitory postsynaptic currents (IPSCs): they followed the reversal potential for chloride ions and they were blocked by the gamma-aminobutyric acid-A (GABAA) receptor antagonist bicuculline. 2. Because of the very low baseline noise it was possible to see discrete levels in the tails of IPSCs that corresponded to the opening of one or more synaptic GABAA receptor channels. "All-points" histograms of the IPSCs showed that the chord conductance of the channels in the tails of the IPSCs was 21.6 +/- 0.6 pS (mean +/- SE, n = 6). 3. The amplitudes of the spontaneous IPSCs were very variable, ranging from 3 to 390 pA at a holding potential of -80 mV. The average of the median amplitudes was -67.5 +/- 5.9 pA (n = 28). The amplitude distributions of the IPSCs were well described by the sum of two lognormal distributions with large SDs. The average of the means of the first lognormal distribution was 27.8 +/- 5.3 pA (n = 10); the average of the SDs was 24.7 +/- 8.1 pA. For the second lognormal distribution these values were 87.0 +/- 13.4 and 33.7 +/- 7.4 pA. An average of 41.8 +/- 6.9% of the IPSCs originated from the first lognormal distribution. 4. The large variability in the amplitudes of spontaneous IPSCs was not the result of presynaptic action potentials because it was not reduced by tetrodotoxin (TTX), Ca(2+)-free extracellular solution, or the combined application of TTX and Mn2+. 5. The time course of the IPSCs from the first and the second lognormal distributions were very similar: averages of the median 20- to 80% rise times were 585 +/- 64 and 488 +/- 28 microseconds, respectively (n = 8), whereas the decays were well described by the sum of two exponential functions, with fast time constants of 8.9 +/- 1.1 (n = 7) and 9.3 +/- 3.3 ms and slow time constants of 29.5 +/- 3.3 and 31.7 +/- 2.6 ms, respectively. 6. The decay of the IPSCs was voltage dependent; it was approximately 3 times slower at a holding potential of +40 mV than at -80 mV (n = 5).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMedDate not supplied

[Reflection of the plastic properties of very simple neuronal assemblies in the statistical characteristics of the spike activity of their elements. Monosynaptically connected neurons].

Changes of cross-correlation histograms (CCH) of impulse trains and of mean interspike intervals (ISI) of monosynaptically connected neurones under changes of interneuronal connection efficiency, neuronal excitability and action on these neurones of independent irregular afferent synaptic inflows, were studied by methods of mathematical and biomathematical modelling of synaptic neuronal interaction (computer-controlled experiment on mollusc neurones). It was shown that statistical of increase of efficiency of monosynaptic excitatory or inhibitory interneuronal connection (amplitude enhancement of corresponding postsynaptic potential) is an increase of the main peak or trough of normalized CCH of impulse trains accompanied by a decrease of mean ISIs of both neurones.

Animals↗

PubMed1992

Postsynaptic spike firing reduces synaptic GABAA responses in hippocampal pyramidal cells.

Using intracellular recording techniques in CA1 cells in the hippocampal slice, we studied the responses of cells to synaptically released and iontophoretically applied GABA. With high-resistance, Cl(-)-filled electrodes, which inverted and enlarged the responses at normal resting potentials, we examined spontaneous GABA-mediated IPSPs. Usually we recorded the spontaneous events in the presence of carbachol (10-25 microM), which significantly increased IPSP frequency and blocked potentially confounding K+ conductances. Following a train of action potentials, spontaneous IPSPs were transiently suppressed. This suppression could not be accounted for by membrane conductance changes following the train or activation of a recurrent circuit. Whole-cell voltage-clamp recordings in the slice indicated that the amplitudes of the spontaneous GABAA inhibitory postsynaptic currents (IPSCs) were also diminished following the action potential train. In some cases BAY K 8644, a Ca2+ channel agonist, enhanced the suppression of IPSPs, while buffering changes in [Ca2+]i with EGTA or BAPTA prevented it. The monosynaptically evoked IPSC in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and dl-2-amino-5-phosphonovaleric acid (APN) was also diminished following a train of action potentials; however, iontophoretically applied GABA responses did not change significantly. These studies suggest that localized physiological changes in postsynaptic [Ca2+]i potently modulate synaptic GABAA inputs and that this modulation may be an important regulatory mechanism in mammalian brain.

Action Potentials↗