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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↗

PubMed2005

Regional hippocampal alteration associated with cognitive deficit following experimental brain injury: a systems, network and cellular evaluation.

Cognitive deficits persist in patients who survive traumatic brain injury (TBI). Lateral fluid percussion brain injury in the mouse, a model of human TBI, results in hippocampal-dependent cognitive impairment, similar to retrograde amnesia often associated with TBI. To identify potential substrates of the cognitive impairment, we evaluated regional neuronal loss, regional hippocampal excitability and inhibitory synaptic transmission. Design-based stereology demonstrated an approximate 40% loss of neurons through all subregions of the hippocampus following injury compared with sham. Input/output curves recorded in slices of injured brain demonstrated increased net synaptic efficacy in the dentate gyrus in concert with decreased net synaptic efficacy and excitatory postsynaptic potential-spike relationship in area CA1 compared with sham slices. Pharmacological agents modulating inhibitory transmission partially restored regional injury-induced alterations in net synaptic efficacy. Both evoked and spontaneous miniature inhibitory postsynaptic currents (mIPSCs) recorded in surviving dentate granule neurons were smaller and less frequent in injured brains than in uninjured brains. Conversely, both evoked and spontaneous mIPSCs recorded in surviving area CA1 pyramidal neurons were larger in injured brains than in uninjured brains. Together, these alterations suggest that regional hippocampal function is altered in the injured brain. This study demonstrates for the first time that brain injury selectively disrupts hippocampal function by causing uniform neuronal loss, inhibitory synaptic dysfunction, and regional, but opposing, shifts in circuit excitability. These changes may contribute to the cognitive impairments that result from brain injury.

Afferent Pathways↗

PubMed2003

Activation of muscarinic receptors inhibits beta-amyloid peptide-induced signaling in cortical slices.

Deposition of fibrillar aggregates of the beta-amyloid peptide (Abeta) is a key pathologic feature during the early stage of Alzheimer's disease. The initial neuronal responses to Abeta in cortical circuits and the regulation of Abeta-induced signaling remain unclear. In this study, we found that exposure of cortical slices to Abeta(1-42) or Abeta(25-35) induced a marked increase in the activation of protein kinase C (PKC) and Ca(2+)/calmodulin-dependent kinase II (CaMKII), two enzymes critically involved in a variety of cellular functions. Activation of M1 muscarinic receptors, but not nicotinic receptors, significantly inhibited the Abeta activation of PKC and CaMKII. Increasing inhibitory transmission mimicked the M1 effect on Abeta, whereas blocking GABA(A) receptors eliminated the M1 action. Moreover, electrophysiological evidence shows that application of Abeta to cortical slices induced action potential firing and enhanced excitatory postsynaptic currents, whereas muscarinic agonists potently increased inhibitory postsynaptic currents. These results suggest that Abeta activates PKC and CaMKII through enhancing excitatory activity in glutamatergic synaptic networks. Activation of M1 receptors inhibits Abeta signaling by enhancing the counteracting GABA(ergic) inhibitory transmission. Thus the muscarinic reversal of the Abeta-induced biochemical and physiological changes provides a potential mechanism for the treatment of Alzheimer's disease with cholinergic enhancers.

Alzheimer Disease↗

PubMed1991

Differential effects of isoquinolinesulfonamide protein kinase inhibitors on CA1 responses in hippocampal slices.

The effects of the isoquinolinesulfonamide protein kinase inhibitors 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) and N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA1004) on CA1 responses in hippocampal slices of the rat were examined to clarify their mode of action, and also to further define the role of Ca(2+) -dependent kinases in long-term potentiation. Initially, the inhibitory potencies of H-7 and HA1004 against both protein kinase C and type II Ca2+/calmodulin-dependent kinase were examined in standard in vitro phosphorylation assays. The apparent Ki values of H-7 and HA1004 for protein kinase C were 9 and 57 microM, respectively. In contrast, the Ki values of H-7 and HA1004 for type II calcium/calmodulin-dependent protein kinase were 156 and 13 microM, respectively. These results indicate that H-7 is a more effective inhibitor of protein kinase C, whereas HA1004 is a more effective inhibitor of type II calcium/calmodulin-dependent protein kinase. Following the induction of long-term potentiation, addition of 50 microM H-7 or HA1004 substantially increased the amplitude of the population spike in a control pathway, while producing no change or a slight increase in the spike amplitude in a previously potentiated long-term potentiation pathway. Moreover, H-7 (50 microM), but not HA1004, produced multiple population spikes in both pathways. Addition of a higher concentration of H-7 (300 microM) reduced the amplitude of the initial population spike but still produced multiple spikes. HA1004 (300 microM) typically produced effects similar to those observed with 50 microM H-7, increasing the amplitude of the control population spike and producing multiple spike activity in both pathways. In contrast to the differential concentration-dependent effects of H-7 on the population spike responses, qualitatively similar effects were observed at both low (50 microM) and high (300 microM) concentrations with regard to synaptic field responses. The initial slope of the population excitatory postsynaptic potential was significantly reduced by H-7, to a similar degree in both pathways. HA1004 produced a modest, but insignificant reduction in both pathways. These results, in conjunction with other reports, suggest that H-7 and HA1004 exert complex concentration-dependent effects with synchronously affect both excitatory and inhibitory synaptic transmission. We hypothesize that reduction of the population excitatory postsynaptic potential and spike (300 microM H-7) is due to reduction of excitatory inputs, whereas enhancement of the population spike amplitude (50 microM H-7) and the production of multiple spikes are due to the reduction of GABA-mediated inhibitory inputs.(ABSTRACT TRUNCATED AT 400 WORDS)

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1963

Physiology of photoreceptor neurons in the abdominal nerve cord of the crayfish.

Nerve fibers which respond to illumination of the sixth abdominal ganglion were isolated by fine dissection from connectives at different levels in the abdominal nerve cord of the crayfish. Only a single photosensitive neuron is found in each connective; its morphological position and pattern of peripheral connections are quite constant from preparation to preparation. These cells are "primary" photoreceptor elements by the following criteria: (1) production of a graded depolarization upon illumination and (2) resetting of the sensory rhythm by interpolated antidromic impulses. They are also secondary interneurons integrating mechanical stimuli which originate from appendages of the tail. Volleys in ipsilateral afferent nerves produce short-latency graded excitatory postsynaptic potentials which initiate discharge of one or two impulses; there is also a higher threshold inhibitory pathway of longer latency and duration. Contralateral afferents mediate only inhibition. Both inhibitory pathways are effective against both spontaneous and evoked discharges. In the dark, spontaneous impulses arise at frequencies between 5 and 15 per second with fairly constant intervals if afferent roots are cut. Since this discharge rhythm is reset by antidromic or orthodromic impulses, it is concluded that an endogenous pacemaker potential is involved. It is postulated that the increase in discharge frequency caused by illumination increases the probability that an inhibitory signal of peripheral origin will be detected.

Animals↗

PubMed1988

Presynaptic inhibition produced by histamine at nicotinic synapses in enteric ganglia.

Intracellular methods were used to record fast excitatory postsynaptic potentials in myenteric neurons of the guinea-pig small intestine in vitro. The excitatory postsynaptic potentials were suppressed by hexamethonium, mimicked by acetylcholine and assumed to be mediated by nicotinic cholinergic receptors. Application of histamine either by addition to the superfusion solution or by focal application from fine-tipped pipettes reversibly reduced the amplitude or abolished the excitatory postsynaptic potentials. Postsynaptic responses to focal application of acetylcholine by pressure ejection from micropipettes were either unaffected or were potentiated by histamine. Failure of histamine to affect antidromic action potentials excluded a local anesthetic action on the presynaptic fibers. Neither 2-methylhistamine nor dimaprit, which are selective H1 and H2 agonists respectively, suppressed the excitatory postsynaptic potentials when applied in concentrations nearly one hundred times greater than the ED50 for histamine. The selective H1 and H2 antagonists, pyrilamine and cimetidine did not suppress the inhibitory action of histamine when applied separately or in combination. Based on these results, the presynaptic receptors involved in this inhibitory mechanism appeared to be of a pharmacologically atypical histamine receptor subtype. The putative histamine agonist, N,alpha-methylhistamine, which has been reported to have high stereoselectivity and activity for a receptor subtype classified as H3, potently reduced or abolished the excitatory postsynaptic potentials. The ED50 for N,alpha-methylhistamine was 8.8 nM compared to an ED50 of 220 nM for histamine. Burimamide, a histamine antagonist with higher activity at putative H3 receptors than H2 receptors, effectively reversed the inhibitory action of histamine on the excitatory postsynaptic potentials.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1992

Barbiturate depression of a K+ dependent inhibitory synapse is independent of dendritic cable filtering.

Technical limitations with intracellular electrophysiological methods usually restrict recording of postsynaptic potentials only from neuronal soma, a site remote from the actual synapse. The intervening dendritic cable interposed between the actual synapse and the site of recording can significantly filter the synaptic signal. Therefore, investigations of drug effect on synaptic mechanisms, based on postsynaptic recordings obtained at the soma, must be interpreted with care. The potential role of dendritic cable filtering in the atypical pentobarbital depression of a K(+)-dependent inhibitory synapse between the P to Nut cell in the posterior packet of the leech was investigated. The effective electrical geometry under the conditions of control and 0.5 mM PNB sufficient to completely abolish the postsynaptic potential were determined from analyses of the membrane charging curves assuming the lumped-soma-short-cable model. Under the control condition, the postsynaptic Nut cell exhibits dendritic dominance with rho = 2.52, normalized equivalent cable length L = 1.08, and a membrane time constant tau o = 52 ms. With phenobarbital application, changes in the geometrical parameters consistent with a decrease in the specific membrane resistance Rm are observed. Simulation of the drug induced change in the electrical geometry demonstrates that the decrease in the post synaptic potential is largely due to the decrease in the soma input resistance and an increase in the cable filter contributes little to the observed depression of the postsynaptic potential. However, the combined effect of the decrease in the input resistance and the increase in the cable filtering of synaptic current is insufficient in explaining the observed total block of the synaptic potential by PNB.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Repetitive axonal discharges elicited by serotonin and intracellular adenosine 3',5'-cyclic monophosphate in the crayfish neuromuscular junction.

Experiments were carried out in the opener muscle of the claw of small crayfish. After pretreatment of the preparation with serotonin (5-HT), application of the membrane permeant analogue of adenosine 3',5'-cyclic monophosphate (cAMP), 8-bromoadenosine 3',5'-monophosphate was capable of evoking reversibly repetitive discharges in the inhibitory and excitatory axon. Reducing phosphodiesterase activity with application of either 3-isobutyl-1-methylxanthine or theophylline also elicited repetitive axonal discharges after 5-HT treatment. Moreover, application of forskolin dissolved in ethanol caused repetitive axonal discharges. The chemically induced presynaptic action potentials were detected mainly by their postsynaptic effects, i.e. by recording inhibitory and excitatory postsynaptic currents in voltage-clamped muscle fibres. In addition, nerve spikes were recorded extracellularly. It is concluded that 5-HT and intraaxonal cAMP alter membrane properties of the efferent axons innervating crayfish muscle.

1-Methyl-3-isobutylxanthine↗

PubMed1995

Presynaptic enhancement of inhibitory synaptic transmission by protein kinases A and C in the rat hippocampus in vitro.

The protein kinase C activator phorbol 12,13-dibutyrate (0.5 microM, PDBu) and the protein kinase A activator forskolin (20 microM) each increased evoked monosynaptic inhibitory postsynaptic current (IPSC) amplitude, without affecting its reversal potential, and increased the frequency of miniature IPSCs (mIPSCs), without affecting their amplitude or kinetics, as assessed with whole-cell recording form CA3 pyramidal cells in hippocampal slice cultures. The effects of forskolin and PDBu on both evoked IPSC amplitude and mIPSC frequency were additive and were antagonized by inhibitors of protein kinases A and C, respectively. The kinase activator-induced increases in mIPSC frequency were quantitatively comparable to the increases in evoked IPSC amplitude. The increases in mIPSC frequency were not attenuated by the voltage-dependent calcium channel blocker Cd2+ (100 microM). We conclude that stimulation of protein kinases A and C potentiates hippocampal inhibitory synaptic transmission through independent presynaptic mechanisms of action. Kinase-induced potentiation of spontaneous release does not require modulation of axon terminal Ca2+ channels. This mechanism may also contribute substantially to the potentiation of evoked release.

Animals↗

PubMed1994

Lasting potentiation of inhibition is associated with an increased number of gamma-aminobutyric acid type A receptors activated during miniature inhibitory postsynaptic currents.

Whole-cell patch-clamp recordings unveiled a substantial increase in the amplitude, but no change in the frequency, of miniature inhibitory postsynaptic currents (mIPSCs) in dentate gyrus granule cells following chronic epilepsy induced by kindling. This novel and persistent enhancement of gamma-aminobutyric acid type A (GABAA) receptor-mediated inhibition lasted for at least 48 hr following its induction. Nearly a doubling of the number of activated functional postsynaptic GABAA receptor channels during mIPSCs without any change in single-channel conductance or kinetics could be demonstrated using nonstationary fluctuation analysis. As postsynaptic GABAA receptors are likely to be pharmacologically saturated by the transmitter concentration in the cleft, incrementing the number of functional receptor channels may be the most effective means to augment inhibition in the mammalian brain.

Animals↗

PubMed1989

Selective depression of synaptic transmission by tetanus toxin: a comparative study on hippocampal and neostriatal slices.

Tetanus toxin reduces the release of neurotransmitters in several brain areas. We have studied the effects of this toxin on the intrinsic and synaptic activity of CA1 hippocampal neurons and of neostriatal cells in the rat by utilizing intracellular and extracellular recordings from slice preparations. Tetanus toxin (10 micrograms/ml) applied by bath produced an increase of the field potentials evoked by the orthodromic stimulation of the CA1 region coupled with the disappearance of the inhibitory period following the first conditioning stimulus. Orthodromically and antidromically activated postsynaptic hyperpolarizing potentials were also decreased and spontaneous bursting activity was observed following the application of tetanus toxin. At this concentration the toxin did not alter excitability in neostriatal cells and in these neurons even 30-50 micrograms/ml of the toxin produced only a slight increase of excitability. Higher concentrations (100 micrograms/ml) of tetanus toxin reduced the excitatory synaptic transmission in the hippocampus as well as in the neostriatum. The toxin (10-100 micrograms/ml) did not alter membrane potential, input resistance or directly evoked firing in both these structures. We conclude that, although the toxin's mechanisms of action in the neostriatum are similar to those operating in the hippocampus (i.e. decrease of inhibitory and/or excitatory inputs), the local synaptic circuits produce differential electrophysiological effects in these two structures.

Action Potentials↗

PubMed2003

Two forms of synaptic plasticity with distinct dependence on age, experience, and NMDA receptor subtype in rat visual cortex.

In visual cortex, NMDA receptor (NMDAR) properties depend primarily on NR2A and NR2B subunits, and NR2 subunit composition changes with age and visual experience. We examined the roles of these NR2 subunits in activity-dependent long-term modification of synaptic responses, which were evoked in layer 2/3 cells by stimulation of layer 4 in rat visual cortical slices. We used theta-burst stimulation (TBS) of presynaptic fibers or low-frequency stimulation paired with postsynaptic depolarization, which has been commonly used to induce NMDAR-dependent long-term potentiation (LTP) in visual cortex. In pyramidal cells, however, TBS produced long-term depression (LTD) at inhibitory synapses rather than LTP at excitatory synapses. This was observed in association with LTP of extracellular field potentials that reflect postsynaptic potentials in a population of cells (field-LTP). This result is inconsistent with the previous view that field-LTP reflects LTP of excitatory connections. However, pairing stimulation produced LTP at excitatory synapses of pyramidal cells frequently during development but rarely in adulthood. In contrast, inhibitory LTD and field-LTP occurred similarly in both developing and mature cortex. Experiments using NR2B selective and NR2 subunit nonselective NMDAR antagonists demonstrated that NR2A- and NR2B-containing NMDARs contribute selectively to inhibitory LTD-field-LTP and excitatory LTP, respectively. In addition, we found that the developmental decline in the NR2B component was paralleled by a decline in the incidence of excitatory LTP, and these declines were both prevented by dark rearing. These results implicate NR2 subunit composition in the regulation of neocortical plasticity and demonstrate differential subunit regulation at inhibitory and excitatory connections.

Age Factors↗

PubMed2000

Electrophysiology of sipatrigine: a lamotrigine derivative exhibiting neuroprotective effects.

Sipatrigine (BW619C89), a derivative of the antiepileptic agent lamotrigine, has potent neuroprotective properties in animal models of cerebral ischemia and head injury. In the present study we investigated the electrophysiological effects of sipatrigine utilizing intracellular current-clamp recordings obtained from striatal spiny neurons in rat corticostriatal slices and whole-cell patch-clamp recordings in isolated striatal neurons. The number of action potentials produced in response to a depolarizing current pulse in the recorded neurons was reduced by sipatrigine (EC(50) 4.5 microM). Although this drug preferentially blocked action potentials in the last part of the depolarizing current pulse, it also decreased the frequency of the first action potentials. Sipatrigine also inhibited tetrodotoxin-sensitive sodium (Na(+)) current recorded from isolated striatal neurons. The EC(50) for this inhibitory action was 7 microM at the holding potential (V(h)) of -65 mV, but 16 microM at V(h) = -105, suggesting a dependence of this pharmacological effect on the membrane potential. Moreover, although the inhibitory action of sipatrigine on Na(+) currents was maximal during high-frequency activation (20 Hz), it could also be detected at low frequencies. The amplitude of excitatory postsynaptic potentials (EPSPs), recorded following stimulation of the corticostriatal pathway, was depressed by sipatrigine (EC(50) 2 microM). This inhibitory action, however, was incomplete; in fact maximal concentrations of this drug reduced EPSP amplitude by only 45%. Sipatrigine produced no increase in paired-pulse facilitation, suggesting that the modulation of a postsynaptic site was the main pharmacological effect of this agent. The inhibition of voltage-dependent Na(+) channels exerted by sipatrigine might account for its depressant effects on both repetitive firing discharge and corticostriatal excitatory transmission. The modulation of Na(+) channels described here, as well as the previously observed inhibition of high-voltage-activated calcium currents, might contribute to the neuroprotective efficacy exerted by this compound in experimental models of in vitro and in vivo ischemia.

Action Potentials↗

PubMed2005

Integrin alpha3beta1 suppresses long-term potentiation at inhibitory synapses on the cerebellar Purkinje neuron.

At the GABAergic synapses between inhibitory interneurons and a Purkinje neuron (PN) in the cerebellum, the postsynaptic depolarization induces the long-term potentiation (called rebound potentiation; RP) of GABAA receptor responsiveness. Here, we show that integrins, a type of cell-adhesion molecules, are involved in the regulation of RP. Integrin activation by Mn2+ impaired the RP induction of GABA responsiveness and mIPSCs in PNs, which was abolished by the function blocking antibody against either integrin alpha3 or beta1 subunit, but not by that against alpha5 or alphaV subunit. Furthermore, overexpression of integrin alpha3 subunit in a PN by itself impaired the RP induction. We also show that Src-family of protein tyrosine kinases mediated the suppressive effect of integrin activity on the RP induction. Thus, the integrin/Src pathway negatively regulates the induction of long-term plasticity at inhibitory synapses on a cerebellar PN.

Animals↗

PubMedDate not supplied

[A possible mechanism of influence of modifiable striatal lateral inhibition on the conditioned selection of motor activity].

A mechanism of the influence of dopamine-evoked modulation of lateral inhibition in the striatum on a conditioned selection of motor activity is proposed. According to suggested modulation rules for inhibitory transmission, action of dopamine on postsynaptic D1 (D2) receptors on striatonigral (striatopallidal) cells promotes long-term depression (potentiation) of inhibitory inputs simultaneously with potentiation (depression) of "strong" excitatory inputs that open NMDA channels on these neurons. If excitatory inputs are "weak" and NMDA channels are closed, modulation rules have opposite signs. Activation of presynaptic D2 (D1) receptors results in a decrease (increase) in GABA release from striatopallidal (striatonigral) axon terminals that innervate striatonigral (striatopallidal) cells. Thereof, dopamine-evoked modulation of lateral inhibition simultaneously strengthens both potentiation (depression) of excitatory inputs to "strongly" activated striatonigral (striatopallidal) neurons rising (reducing) their activity, and depression (potentiation) of excitatory inputs to "weakly" activated striatonigral (striatopallidal) neurons reducing (rising) their activity. Subsequent reorganization of neuronal activity in the cortico-basal-ganglia-thalamocortical loop promotes a conditioned selection of motor reaction because of the further increase (decrease) in activity of those motocortical neurons that "strongly" ("weakly") activated the striatum during dopamine release in response to conditioned stimulus.

Conditioning, Classical↗

PubMed1988

Seasonal changes in inhibitory currents in rat hippocampus.

Spontaneous inhibitory postsynaptic currents were recorded in voltage-clamped neurons (clamp potential -60 to -70 mV) in the pyramidal cell layer of the CA1 region of hippocampal slices from 3- to 4-month-old rats. The average time constant of decay of the currents progressively increased from March (early autumn) to July (mid-winter) and then declined progressively from July to November (late spring). The changes were statistically significant. It is suggested that such seasonal changes in the time course of inhibitory postsynaptic currents may have behavioural consequences and could explain the reported seasonal variations in the occurrence of disorders such as mania.

Animals↗

PubMed2004

[Effects of etomidate on local synaptic transmission in substantia gelatinosa neurons of the adult rat spinal cord].

By using blind spinal slice whole-cell patch-clamp technique, we observed the influence of etomidate (ET) on synaptic transmission in substantia gelatinosa neurons of the adult rat spinal cord. Male adult Sprague-Dawley rats (7~8 weeks old) were anaesthetized with urethane (1.2 g/kg, i.p.), and then lumbosacral laminectomy was performed. The lumbosacral spinal cord (L1~S3) was removed and placed in preoxygenated Krebs solution at 1~3 degrees C. After cutting all of the ventral and dorsal roots, the pia-arachnoid membrane was removed. The spinal cord was mounted on a vibrating microslicer and then a 500 microm thick transverse slice was cut. The slice was placed on a nylon mesh in the recording chamber, and then perfused at a rate of 15~20 ml/min with Krebs solution saturated with 95% O2 and 5% CO2, and maintained at 36+/-1 degrees C. Substantia gelatinosa neurons were identified by their location. Under a binocular microscope and with transmitted illumination, the substantia gelatinosa was clearly discernible as a relatively translucent band across the dorsal horn. The resistance of patch clamp electrodes was 8~12 Msigma. Signals were gained by using an Axopatch 200B amplifier with low-passfiltered at 5 kHz, and digitized at 333 kHz with an A/D converter. The results are as follows. (1) To see whether or not ET has any effects on the local miniature excitatory postsynaptic currents (mEPSC), the holding potential was set up at -70 mV. Under such a condition extracellular superfusion was made with 1 micromol/L TTX for 2 min first, which was followed by consistent application of 500 micromol/L ET and 1 micromol/L TTX for 1 min. It was shown that ET did not influence the decay time, frequency and amplitude of mEPSC, when compared to the control. (2) To see whether or not ET has any effects on the local miniature inhibitory postsynaptic currents (mIPSC) mediated by GABA(A) receptor, the holding potential was set up at 0 mV. Under this condition extracellular superfusion was made with 1 micromol/L TTX and 1 micromol/L strychnine, an antagonist of glycine receptor, for 2 min, and then with consistent application of 50 micromol/L ET, 1 micromol/L TTX and 1 micromol/L strychnine for 1 min. ET prolonged the decay time of GABAergic mIPSC by 45.57+/-12.46% (P<0.05), but did not influence the frequency and amplitude of GABAergic mIPSC, when compared with the control. (3) To see whether or not ET has any effects on the local mIPSC mediated by glycine receptor, the holding potential was also set up at 0 mV, and under this condition extracellular superfusion was made with 1 mmol/L TTX and 10 mmol/L bicuculline, an antagonist also set up at 0 mV, and under this condition extracellular superfusion was made with 1 micromol/L TTX and 10 micromol/L bicuculline, an antagonist of GABA(A) receptor, for 2 min, and then with consistent application of 50 micromol/L ET, 1 micromol/L TTX and 10 micromol/L bicuculline for 1 min. ET had no effects on decay time, frequency and amplitude of glycinergic mIPSC. The above-mentioned results show that ET plays anesthetic or analgesic roles by modulating the decay time of GABAergic mIPSC, i.e. by prolonging the mean open time of GABA(A) receptors, however, ET has no direct effect on local excitatory synaptic transmission in substantia gelatinosa neurons of the adult rat spinal cord.

Anesthetics, Intravenous↗

PubMed1993

Cholinergic modulation of synaptic inhibition in the guinea pig hippocampus in vitro: excitation of GABAergic interneurons and inhibition of GABA-release.

1. The effect of cholinergic receptor activation on gamma-aminobutyric acid (GABA)-mediated inhibitory synaptic transmission was investigated in voltage-clamped CA1 pyramidal neurons (HPNs) in the guinea pig hippocampal slice preparation. 2. The cholinergic agonist carbachol (1-10 microM) induced a prominent and sustained increase in the frequency and amplitudes of spontaneous inhibitory postsynaptic currents (IPSCs) in Cl(-)-loaded HPNs. The potentiation of spontaneous IPSCs was not dependent on excitatory synaptic transmission but was blocked by atropine (1 microM). 3. Monosynaptically evoked IPSCs were reversibly depressed by carbachol (10 microM). 4. The frequency of miniature IPSCs recorded in the presence of tetrodotoxin (0.6 or 1.2 microM) was reduced by carbachol (10 or 20 microM) in an atropine-sensitive manner. 5. We conclude that, while cholinergic receptor activation directly excites hippocampal GABAergic interneurons, it has, in addition, a suppressant effect on the synaptic release mechanism at GABAergic terminals. This dual modulatory pattern could explain the suppression of evoked IPSCs despite enhanced spontaneous transmission.

Animals↗

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