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PubMed1996

Physiological and pharmacological profile of trans-azetidine-2,4-dicarboxylic acid: metabotropic glutamate receptor agonism and effects on long-term potentiation.

In this study, we biochemically analysed the effects of the novel metabotropic glutamate receptor agonist trans-azetidine-2,4-dicarboxylic acid and examined its role in hippocampal long-term potentiation. In cell lines expressing metabotropic receptor 1 or 5 subtypes, the compound stimulated phosphoinositide hydrolysis with EC50 values of 189.4 +/- 6.4 and 32.2 +/- 8.3 microM, respectively. In hippocampal slices, trans-azetidine-2,4-dicarboxylic acid also increased phosphoinositide hydrolysis, yet failed to show any effect on forskolin-stimulated formation of cyclic AMP, even if 1 mM azetidine was applied. Since trans-azetidine-2,4-dicarboxylic acid (20 mM in 5 microliters) injected cerebroventricularly prolongs long-term potentiation induced by weak tetanization, a possible interaction with N-methyl-D-aspartate receptors was investigated using patch-clamp techniques. Neither facilitation of N-methyl-D-aspartate (500 microM) currents nor induction of non-specific currents was observed in the presence of 50 and 500 microM azetidine. Strong tetanus-induced long-term potentiation in the dentate gyrus of freely moving rats was not influenced by azetidine. In combination with the antagonist (R,S)-alpha-methyl-4-carboxyphenylglycine (200 mM in 5 microliters), however, the potentiation was attenuated and returned to baseline within 90 min. Blockade of N-methyl-D-aspartate receptors using 2-amino-5-phosphonopentanoate (20 mM in 5 microliters) prevented the potentiation in controls, but not in the azetidine group, where normal potentiation was observed for both the population spike amplitude and the excitatory postsynaptic potential. These data suggest that (i) trans-azetidine-2,4- dicarboxylic acid is an agonist at glutamate metabotropic receptors; (ii) a facilitation of induction and maintenance of long-term potentiation via N-methyl-D-aspartate receptors seems unlikely; and (iii) pharmacological activation of metabotropic receptors prior to tetanization appears to bypass the N-methyl-D-aspartate receptor dependence of the potentiation. In conclusion, a role for metabotropic glutamate receptors in both short-term and long-term potentiation is indicated by these data.

Animals↗
PubMed1995

Action of GP 47779, the active metabolite of oxcarbazepine, on the corticostriatal system. I. Modulation of corticostriatal synaptic transmission.

Oxcarbazepine (OCBZ) is the keto-analogue of carbamazepine (CBZ). In humans, OCBZ is rapidly and almost completely metabolized to 10, 11-dihydro-10-hydroxy-CBZ (GP 47779), the main metabolite responsible for the drug's antiepileptic activity. The corticostriatal pathway is involved in the propagation of epileptic discharges. We characterized the electrophysiological effects of GP 47779 on striatal neurons by making intracellular recordings from corticostriatal slices. GP 47779 (3-100 microM) produced a dose-dependent inhibition of glutamatergic excitatory postsynaptic potentials (EPSPs). This effect was not coupled either with changes of the membrane potential of these cells or with alterations of their postsynaptic sensitivity to excitatory amino acids (EAA) suggesting a presynaptic site of action. GP 47779 reduced the current-evoked firing discharge only at concentrations > 100 microM. GP 47779 did not affect the presynaptic inhibitory action of adenosine, showing that presynaptic adenosine receptors were not implicated in the GP 47779-mediated reduction of corticostriatal EPSPs. Our data indicate that GP 47779 apparently acts directly on corticostriatal terminals to reduce the release of EAA, probably by inhibiting high-voltage-activated (HVA) calcium (Ca2+) currents (described in the accompanying article). The inhibitory action of GP 47779 on corticostriatal transmission may contribute to the antiepileptic effects of this drug.

Adenosine↗
PubMed1988

Long-term potentiation at nicotinic synapses in the rat superior cervical ganglion.

1. Nicotinic fast excitatory postsynaptic potentials (fast EPSPs) were recorded intracellularly from postganglionic neurones in the isolated rat superior cervical ganglion. 2. An hours-long potentiation of the fast EPSP could be induced by brief tetanic stimulation of the preganglionic nerve (5 Hz for 5 s to 20 Hz for 20 s). While long-term potentiation (LTP) can be detected in every ganglion by extracellular techniques, LTP was induced in only two-thirds of the nicotinic synaptic responses. 3. Muscarinic blockade with atropine did not prevent LTP of the fast EPSP. 4. LTP of the fast EPSP did not correlate with changes in input resistance nor cell potential, as recorded in the soma. 5. The formation of nicotinic LTP appeared to depend upon stimulation of the nerve terminals. Non-synaptic tetanic depolarization of the postganglionic neurone, effected by injecting depolarizing current pulses through the intracellular microelectrode, was not sufficient. LTP could be induced by synaptic tetani in two-thirds of the same neurones. 6. The response to exogenous 1,1-dimethyl-4-phenylpiperazinium (DMPP), a selective nicotinic agonist, was not increased during nicotinic synaptic LTP. This was true whether DMPP was applied by pressure-ejection from an extracellular micropipette during intracellular recording, or by brief superfusion during sucrose-gap recording of postganglionic responses. 7. Responses to exogenous acetylcholine and carbachol were increased during nicotinic LTP when these non-selective cholinergic agonists were applied by pressure-ejection during intracellular recording. However, the potentiation of the fast EPSP was always at least twofold greater than the potentiation of the response to these exogenous agonists. 8. Potentiation of the responses to acetylcholine and carbachol may have been due to long-term enhancement of muscarinic responses. Thus, no postsynaptic basis for nicotinic LTP was uncovered in these studies.

Acetylcholine↗
PubMed1986

The effects of high Mg2+-to-Ca2+ ratios on frequency potentiation in hippocampal slices of young and aged rats.

In some central systems, excitatory postsynaptic potential (EPSP) amplitude increases substantially during repetitive synaptic stimulation ("frequency potentiation"), as does the probability of spike generation. An apparently analogous phenomenon at the neuromuscular junction ("frequency facilitation") depends on residual Ca2+ in nerve terminals. However, the mechanisms of central frequency potentiation are not completely defined and it is therefore not clear whether the patterns of Ca2+-dependent synaptic plasticity are fully analogous in central and peripheral systems. In addition, an age-related deficit in hippocampal frequency potentiation has been previously described, and the degree of sensitivity of this deficit to Mg2+-to-Ca2+ balance could yield important insights into its nature. In these studies, we used the hippocampal slice preparation to examine the effects of varying Mg2+-to-Ca2+ ratios in the artificial cerebrospinal fluid (ACF) on frequency potentiation in aged and young rats. Extracellular and intracellular methods were used to assess the responses of hippocampal CA1 neurons during orthodromic stimulation of the monosynaptic Schaffer-commissural pathway. In experiment 1, frequency potentiation of the hippocampal population spike during 7-Hz stimulation was found to be significantly greater in an ACF with a high Mg2+-to-Ca2+ ratio (2.7) than in an ACF with a normal Mg2+-to-Ca2+ ratio (0.5), for both young and aged rat slices. Aged slices exhibited less frequency potentiation than young in both media. In experiment 2, the field EPSP and population spike were monitored concurrently, and the differences in Mg2+-to-Ca2+ ratio between the high Mg2+-to-Ca2+ ACF ratio (2.0) and normal Mg2+-to-Ca2+ ACF ratio (1.0) were reduced, to determine whether aged and young brains differed in sensitivity to smaller variations in Mg2+-to-Ca2+ balance. Under these conditions, the effects of high Mg2+-to-Ca2+ ratios on frequency potentiation (at 7 Hz) were found to be most pronounced in aged rat slices, particularly for potentiation of the spike. No effects were seen of age or Mg2+-to-Ca2+ ratios on presynaptic fiber volley amplitudes. Field EPSP (but not spike) amplitudes were reduced with aging, in an input-output (I/O) stimulation series at control frequency (0.2 Hz). However, the high Mg2+-to-Ca2+ ACF ratio of (2.0), which improved field EPSP frequency potentiation, did not decrease control field EPSP amplitudes in the I/O series. Therefore, the effects of high MG2+-to-Ca2+ ACF ratio on brain frequency potentiation seem to be mediated in part by mechanisms other than the classical reduction of release probability.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1993

Effects of transient depolarizing potentials on the firing rate of cat neocortical neurons.

1. The effects of excitatory postsynaptic potentials (EPSPs) on interspike intervals (ISIs) of neocortical neurons can be mimicked by pulse potentials (PPs) produced by current injection. The present report documents the dependence of the ISI shortening on the amplitudes of PPs and EPSPs and on the firing rate of the affected neuron. 2. In rhythmically firing necortical neurons, the ISI shortenings caused by PPs arriving at specific times in the ISI can be described by a shortening-delay (S-D) curve. The S-D curve yields three measures of the PPs' ability to shorten the ISI: 1) the mean ISI shortening, S; 2) the maximum shortening, Smax; and 3) the effective interval, defined as the portion of the ISI in which the PP consistently shortens the ISI. For PPs ranging between 80 microV and 3.6 mV (and cells firing at 25 imp/s), the mean shortening increased with amplitude h as S (ms) = 1.2*h (mV)1.24 (r = 0.94; P < 0.01). Smax increased linearly with amplitude as 4.9 ms/mV (r = 0.86, P < 0.01). The effective interval (as a percentage of the ISI) increased slightly with PP amplitude and had a mean value of 65 +/- 21% (mean +/- SD). 3. S-D curves obtained with stimulus-evoked EPSPs varied with EPSP amplitude in a manner similar to those of PPs. The relations obtained for stimulus-evoked EPSPs were not statistically different from those obtained for PPs in the same cells. 4. To determine the effect of firing rate. PPs were applied while neurons fired at frequencies ranging from 8 to 71 imp/s. Both S and Smax were approximately inversely proportional to the baseline firing rate (fo) and could be described as: S or Smax = kfo-m. The mean value of the exponent m (+/- SD) was 0.96 +/- 0.25 for S and 1.2 +/- 0.4 for Smax. These values were not statistically different from a value of 1 (1 group, 2-tailed t test). The effective interval did not vary significantly with firing rate. 5. The dependence of S on PP amplitude and baseline firing rate was incorporated into an expression for the average change in firing rate (delta f) produced by PPs occurring at rate fs: delta f = 0.03 h1.24 fs. The delta f increased with PP amplitude but did not vary significantly with the baseline firing rate. The values of delta f calculated from the S-D curves matched the values that were computed directly from the spike trains.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1997

Neural mechanisms of reflex reversal in coxo-basipodite depressor motor neurons of the crayfish.

The in vitro preparation of the fifth thoracic ganglion of the crayfish was used to investigate the mechanisms underlying the reflex reversal in a sensory-motor pathway. Sensory afferent neurons from the coxo-basipodite chordotonal organ (CBCO), which senses vertical movements of the limb, connect monosynaptically with basal limb motor neurons (MNs). In tonically active preparation, stretching the CBCO (corresponding to downward movements of the leg) stimulates the levator MNs, whereas releasing the CBCO activates the depressor (Dep) MNs. These reflexes, opposed to the imposed movement, are termed resistance reflexes. By contrast, during fictive locomotion, the reflexes are reversed and termed assistance reflexes. Intracellular recordings from all 12 Dep MNs were performed in single experiments. It allowed us to characterize three types of Dep MNs according to their response to CBCO imposed step-and-ramp movements: 8 of the 12 Dep MNs are resistance MNs that are depolarized during release of the CBCO and are connected monosynaptically to release-sensitive CBCO neurons; 1 Dep MN is an assistance MN that is depolarized during stretching of the CBCO and is connected monosynaptically to exclusively velocity-coding stretch-sensitive CBCO neurons; in our experimental conditions, 3 Dep MNs do not display any response to CBCO stimulation. Assistance reflex interneurons (ARINs), involved in polysynaptic assistance reflexes recorded from depressor MNs, are presented. During low-velocity (0.05 mm/s) stretching ramps imposed on the CBCO, ARINs display compound excitatory postsynaptic potentials (EPSPs), whereas during high-velocity (0.25 mm/s) ramps, they display a mixed excitatory and inhibitory response. Whereas a single MN generally receives monosynaptic EPSPs from three to six CBCO neurons, ARINs receive monosynaptic EPSPs from up to eight velocity-coding stretch-sensitive CBCO neurons. In addition, ARINs receive disynaptic inhibitory phasic inputs from stretch-sensitive CBCO afferents. Injection of a depolarizing current pulse into ARINs elicits a fast transient voltage-dependent depolarization. Its time to peak decreases, and its peak amplitude increases with increasing current intensity. ARINs likely are to be connected directly to Dep MNs. The synaptic delay between these nonspiking ARINs and Dep MNs is short (<2 ms) and constant. The postsynaptic EPSP amplitude increases with increasing current pulse intensity injected into ARIN. The dual sensory control (excitatory and inhibitory) makes it likely that ARIN represents a key element in reflex reversal control.

Adaptation, Physiological↗
PubMed1991

Effects of a benzodiazepine antagonist, Ro 15-1788, on hippocampal field potentials in freely moving rats.

Effects of a benzodiazepine receptor agonist (diazepam) and an antagonist (Ro 15-1788, flumazenil) administered separately or in combination on field potentials recorded from the hippocampal dentate area were examined in unanesthetized, unrestrained rats. Population excitatory postsynaptic potentials (EPSPs) evoked by stimulation of the perforant path were depressed significantly by diazepam (4 mg/kg, i.p.). However, diazepam did not affect the firing (spike) threshold of dentate granule cells. The injection of Ro 15-1788 (4 mg/kg, i.p.) alone affected neither excitatory synaptic transmission nor population spike threshold. Strength of gamma-amino butyric acid-mediated recurrent inhibition as measured by the paired-pulse technique was potentiated by diazepam but unaffected by Ro 15-1788. However, the diazepam-enhanced inhibition was reversed by a subsequent administration of Ro 15-1788. Previous studies indicate that Ro 15-1788 acts not only as a selective benzodiazepine antagonist but also as a partial agonist-antagonist or an inverse agonist depending probably on doses. The present study demonstrated that Ro 15-1788 acted as a pure antagonist at low doses. These data suggest that the clinical use of Ro 15-1788 at high doses against comas induced by unidentified drugs could worsen the conditions and that low doses are recommendable for initial treatments because of its pure antagonist action.

Animals↗
PubMed1997

Stimulation within the rostral ventrolateral medulla can evoke monosynaptic GABAergic IPSPs in sympathetic preganglionic neurons in vitro.

The inhibitory responses of identified sympathetic preganglionic neurons (SPNs) to stimulation within the rostral ventrolateral medulla (RVLM) were studied to determine their nature and pharmacology. Whole cell patch-clamp recordings were made from 36 SPNs in the upper thoracic segments of the spinal cord in a neonatal rat brain stem-spinal cord preparation. Neurons were identified as SPNs on the basis of their antidromic activation after stimulation of the ipsilateral segmental ventral root and their morphology and location in the intermediolateral cell column and intercalated nucleus. In all SPNs, electrical stimulation of the RVLM evoked fast excitatory postsynaptic potentials (EPSPs) that were mediated by non-N-methyl-D-aspartate (NMDA) and NMDA receptors. These excitatory responses were the most prominent response in control artificial cerebrospinal fluid and have been studied previously. In 22 of the SPNs, RVLM stimulation also elicited fast inhibitory postsynaptic potentials (IPSPs), which increased in amplitude as the membrane was depolarized. Five of these neurons were not studied further as they responded occasionally with IPSPs that had highly variable onset latencies indicating the involvement of a polysynaptic pathway. In the remaining SPNs (n = 17), the evoked IPSPs persisted in the presence of the excitatory amino acid antagonists 6-cyano-7-nitroquinoxaline-2,3,-dione and D,L-2-amino-5-phosphonopentanoic acid. In eight of these SPNs, it was necessary to block the EPSPs to reveal the IPSPs. In the 7 SPNs tested, the onset latencies of the IPSPs were not significantly different from the onset latencies of the fast EPSPs. The low sweep-to-sweep fluctuations in onset latency of individual IPSPs (absolute average deviation: 0.4 ms) indicated that the IPSPs were elicited by activation of a monosynaptic pathway. The amplitudes of the IPSPs decreased in amplitude as the membrane was hyperpolarized and reversed in polarity at -70.3 +/- 1.7 mV (mean +/- SD), which was close to the equilibrium potential for chloride ions. In addition, in seven SPNs, bath applications of 5 microM bicuculline, a gamma-aminobuturic acid-A (GABAA) antagonist, abolished or reduced the evoked IPSPs. Five SPNs also were studied that displayed ongoing IPSPs. The amplitudes of these IPSPs increased with membrane depolarization and were blocked by bath applications of 5 microM bicuculline, suggesting that they also were mediated by activation of GABAA receptors. These results demonstrate the existence of a bulbospinal GABAergic pathway impinging directly onto SPNs. This pathway may be tonically active in the neonatal rat brain stem-spinal cord preparation.

Adrenergic Fibers↗
PubMed1989

Neural mechanism generating firing patterns in jaw motoneurons during the food-induced response in Aplysia kurodai. I. Identification and characterization of premotor neurons.

1. In each right and left buccal ganglia of Aplysia kurodai, we identified 4 premotor neurons impinging on the ipsilateral jaw-closing and -opening motoneurons. Three of them (MA1 neurons) had features of multifunctional neurons. Current-induced spikes in the MA1 neurons produced excitatory junction potentials (EJPs) in the buccal muscle fibers. In addition, tactile stimulation of the buccal muscle surface produced a train of spikes in the MA1 neurons without synaptic input. The other neuron (MA2) had only a premotor function. 2. The MA1 and MA2 neurons had similar synaptic effects on the jaw-closing and -opening motoneurons. Current-induced spikes in the premotor neurons gave rise to monosynaptic inhibitory postsynaptic potentials (IPSPs) in the ipsilateral jaw-closing motoneurons. Simultaneously, spikes in one of the MA1 neurons and the MA2 also gave rise to monosynaptic excitatory postsynaptic potentials (EPSPs) in the ipsilateral jaw-opening motoneuron. 3. The IPSPs and the EPSPs induced by spikes in the premotor neurons were reversibly blocked by d-tubocurarine and hexamethonium, respectively, suggesting that the MA1 and MA2 neurons are cholinergic. 4. When depolarizing and hyperpolarizing current pulses were passed into one premotor neuron, attenuated but similar potential changes were produced in another randomly selected premotor neuron in the same ganglion, suggesting that they are electronically coupled.

Animals↗
PubMed1993

Epileptogenesis in chronically injured cortex: in vitro studies.

1. Field potentials and intracellular activities were examined in neocortical slices obtained through areas of chronic cortical injury produced by cortical undercutting and transcortical lesions made in vivo 7-122 days before the terminal in vitro slice experiment. 2. Abnormal field potentials characterized by long- and variable-latency multiphasic events could be evoked by layer VI-white matter or subpial stimulation in 9 of 15 animals that had adequate partial cortical isolations. These "epileptiform" field potentials were recorded in layers II-V and propagated across the cortex. They appeared at threshold in an all-or-none fashion and, in most slices, could be blocked by increasing stimulus intensity. In one slice, spontaneous epileptiform events occurred that were similar to those evoked by extracellular stimulation. 3. Intracellular activities during the epileptiform field potentials consisted of polyphasic synaptic events that were predominantly depolarizing and that could last < or = 400-500 ms, synchronous with the field potential activities. A variety of observations suggested that the neuronal activities underlying epileptiform field potentials were relatively asynchronous and much less intense than those previously found in chemically induced epileptogenesis within the neocortex. 4. Inhibitory postsynaptic potentials (IPSPs) were not prominent in neurons when threshold stimuli evoked epileptiform events; however, suprathreshold stimuli could elicit biphasic IPSPs and block the long-latency polysynaptic activity and abnormal field potential in most slices. Depolarizing components of the polysynaptic activity had the appearance of excitatory postsynaptic potentials in terms of their responses to alterations in membrane potential. 5. Comparison of spike parameters in layer V neurons of epileptogenic slices with those in control layer V neurons showed no significant differences in spike height, threshold, duration, or rise time. Resting membrane potentials were also not significantly different. 6. There was a highly significant difference in input resistance (RN) between layer V neurons in control and injured slices; the mean value for neurons in lesioned cortex was 68.1 M omega, whereas that in control cells was 30.5 M omega. There was also a significant prolongation of the slow membrane time constant in neurons of injured cortex (19.4 ms) as opposed to that in control cells (12.2 ms), suggesting that a change in specific resistivity or capacitance contributed to the higher RNS. 7. The relationship between adapted spike frequency and applied current (f-I slope) was steeper in layer V neurons from injured cortical slices (44.3 Hz/nA) than in normal layer V cells (28.2 Hz/nA).(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1991

[Effects of pentobarbital on hippocampal dentate field potentials in unrestrained rats].

The field potential technique was used to examine the effects of pentobarbital (40 mg.kg-1, ip) on the excitatory synaptic transmission and synchronous discharge of granule cells in the hippocampal dentate area of unrestrained rats. Two components of the dentate field potential evoked by perforant path stimulation were analyzed; the population EPSP and the population spike representing an extracellular excitatory postsynaptic potential and synchronous discharge, respectively. The rate of rise (slope) of the population EPSP decreased within 5 min after an injection of pentobarbital. This depression of excitatory synaptic transmission lasted for about 2 hrs and then recovered to near the pre-drug control level within 3 hrs. The ratio of population spike amplitude to population EPSP slope (S/E ratio) was calculated to estimate the readiness of granule cells for synchronous discharge. After an injection of pentobarbital the S/E ratio increased for 2 hrs, indicating that the synchronous discharge of granule cells was facilitated by the drug in spite of the depression of excitatory synaptic transmission. Under pentobarbital anesthesia, the onset and peak latencies of population spikes were prolonged for 0.2-0.4 msec.

Animals↗
PubMed1995

Tachykininergic slow depolarization of motoneurones evoked by descending fibres in the neonatal rat spinal cord.

1. In the isolated spinal cord of the neonatal rat, repetitive electrical stimulation of the upper cervical region elicited a prolonged depolarization of lumbar motoneurones (L3-5) lasting 1-2 min, which was recorded extracellularly from ventral roots, or intracellularly. 2. This depolarizing response was markedly depressed by the excitatory amino acid receptor antagonists D-(-)-2-amino-5-phosphonovaleric acid (D-APV, 30 microM) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM). The remaining response was further depressed by a 5-hydroxytryptamine (5-HT) receptor antagonist, ketanserin (3 microM). 3. In the presence of these antagonists, a small part of the depolarizing response of slow time course remained, and this response was partially blocked by the tachykinin NK1 receptor antagonists GR71251 (0.3-5 microM) and RP67580 (0.3-1 microM). In contrast, RP68651 (0.3-1 microM), the inactive enantiomer of RP67580, had no effect on the depolarizing response. 4. The slow depolarizing response in the presence of D-APV, CNQX and ketanserin was markedly potentiated by a peptidase inhibitor, thiorphan (1 microM). 5. This descending fibre-evoked slow depolarization became smaller after prolonged treatment (5-7 h) with 5,7-dihydroxytryptamine (10 microM), a neurotoxin for 5-HT neurones. Under such conditions, the effects of thiorphan and GR71251 on the slow depolarization were virtually absent. 6. Under the action of D-APV, CNQX and ketanserin, applications of tachykinins, substance P and neurokinin A produced depolarizing responses of lumbar motoneurones, and the responses were depressed by GR71251 and potentiated by thiorphan. 7. These results suggest that tachykinins contained in serotonergic fibres serve as neurotransmitters mediating the descending fibre-evoked slow excitatory postsynaptic potentials in motoneurones.

5,7-Dihydroxytryptamine↗
PubMed1990

Long-term enhancement of postsynaptic excitability after brief exposure to Mg2(+)-free medium in normal and epileptic mice.

Brief exposure to Mg2(+)-free medium (MFM) enhanced the population response of CA1 neurons to stratum radiatum stimulation in hippocampal slices from normal (+/?) and epileptic tottering (tg/tg) mice. The enhancement was maintained in both groups for at least 2 h following reperfusion with normal medium (NM). Excitability curves obtained from the extracellular records suggest that, while both synaptic activation and postsynaptic excitability are enhanced during MFM perfusion, only the latter enhancement is maintained at significant levels after reperfusion with NM. The long-term increase in postsynaptic excitability was comparable in strength to that produced by long-term potentiation (LTP) inducing tetanic stimuli, was accompanied by an increase in the slope of the population spike/field excitatory postsynaptic potential (PS/fEPSP) curve and did not appear to depend on the induction of epileptiform activity by MFM. Both the short- and the long-term effects of MFM on synaptic activation and postsynaptic excitability were qualitatively similar in normal and epileptic mice and any quantitative differences were not statistically significant. Thus, epileptogenesis in the tottering mutant may not involve a change in the NMDA receptor-mediated control of excitability, at least in the CA1 area of hippocampus.

Action Potentials↗
PubMed1997

Depression of A and C fibre-evoked segmental reflexes by morphine and clonidine in the in vitro spinal cord of the neonatal rat.

1. Population synaptic responses of motoneurones were recorded from a ventral root following electrical stimulation of the corresponding lumbar dorsal root in neonatal rat hemisected spinal cord preparations in vitro. Two levels of electrical stimulation were used to elicit dorsal root compound action potentials that contained either an A fibre component alone or both A and C fibre components. The effects of centrally acting analgesics and an N-methyl-D-aspartate (NMDA) receptor antagonist were tested on synaptic responses produced by these two levels of stimulation. 2. At stimulus intensities below four times threshold (T) there was no C fibre component in the dorsal root compound action potential. Responses to a single pulse at 3T (the low intensity excitatory postsynaptic potential (e.p.s.p.)), a train of five pulses at 2T (the train e.p.s.p.) and a single supramaximal pulse (the high intensity e.p.s.p.) were used to compare the depressant actions of morphine, clonidine and the competitive NMDA antagonist CGP40116 (D-(E)-2- amino-4-methyl-5-phosphono-pentenoic acid). The train e.p.s.p. (mean half-time to decay 5 +/- 0.6 s, n = 6) had a similar profile to the high intensity e.p.s.p. (mean half-time to decay 6.8 +/- 0.7, n = 8). 3. The monosynaptic compound action potential of motoneurones (MSR) was resistant to all three drugs irrespective of the intensity of dorsal root stimulation. The low intensity e.p.s.p., the train e.p.s.p. and the high intensity e.p.s.p. were depressed by all three drugs. The EC50 values for depression by morphine were 79 +/- 1 nM (n = 8) for the high intensity e.p.s.p. and 99 +/- 1 nM (n = 4) for the low intensity e.p.s.p. The corresponding values for clonidine were 25 +/- 1 nM (n = 8) and 9 +/- 1 nM (n = 4) and those for CGP40116 were 860 +/- 1.3 nM (n = 4) and 76 +/- 1.1 nM (n = 4). 4. The depressant profile of the NMDA antagonist, having the least depressant activity on the C fibre-mediated response, was different from that of the two analgesics. CGP40116 (3 microM) depressed the high intensity e.p.s.p. to 62 +/- 8%, the low intensity e.p.s.p. to 22 +/- 4% and the train e.p.s.p. to 16 +/- 2% of control values. 5. The depressant actions of morphine were fully reversed by naloxone (1 microM) and those of clonidine were fully reversed by atipamezole (1 microM). 6. These results show that, in contrast to previous findings, activation of primary afferent C fibres in dorsal roots is not required for generation of morphine- or clonidine-sensitive synaptic responses in ventral roots of this in vitro preparation.

2-Amino-5-phosphonovalerate↗
PubMed1991

Probabilistic secretion of quanta from nerve terminals in avian ciliary ganglia modulated by adenosine.

1. The effects of adenosine on the probability of secretion of acetylcholine quanta and on presynaptic and postsynaptic action potentials was examined in the post-hatched avian ciliary ganglion. 2. Adenosine (20 microM) reduced the average size of the excitatory postsynaptic potential (EPSP) by 33%. This was due to a decrease in quantal content of the EPSP (m). The effect was blocked by theophylline (50 microM). 3. Adenosine deaminase (2.5 i.u./ml) increased the size of the EPSP by 70%, suggesting that endogenous adenosine modulates synaptic transmission in the ciliary ganglion. However, theophylline (20-100 microM) did not affect the EPSP in a low [Ca2+]o of 1 mM and high [Mg2+]o of 6 mM. 4. Plateau-type action potentials with a large calcium component were generated in the ciliary neurones by bathing the ganglion in tetraethylammonium ions (TEA, 10 mM). Adenosine (20 microM) reduced the duration of these action potentials on short exposures (less than 20 min) but increased the duration on longer exposure (greater than 30 min). Adenosine did not affect the normal action potential recorded in the absence of TEA. 5. Adenosine (20 microM) hyperpolarized the nerve terminal and as a consequence increased the size of the presynaptic action potential and reduced its after-hyperpolarization. 6. Plateau-type action potentials with a large calcium component were generated in the nerve terminals using TEA (10 mM). The duration of these action potentials was significantly reduced by adenosine (20 microM). 7. Adenosines action on nerve terminals, to hyperpolarize the membrane and reduce calcium influx, may contribute to its effect in reducing m of the EPSP.

Acetylcholine↗
PubMed2000

Kainate receptor-mediated presynaptic inhibition at the mouse hippocampal mossy fibre synapse.

1. The presynaptic action of kainate (KA) receptor activation at the mossy fibre-CA3 synapse was examined using fluorescence measurement of presynaptic Ca2+ influx as well as electrophysiological recordings in mouse hippocampal slices. 2. Bath application of a low concentration (0.2 microM) of KA reversibly increased the amplitude of presynaptic volley evoked by stimulation of mossy fibres to 146 +/- 6 % of control (n = 6), whereas it reduced the field excitatory postsynaptic potential (EPSPs) to 30 +/- 4 %. 3. The potentiating effect of KA on the presynaptic volleys was also observed in Ca2+-free solution, and was partly antagonized by (2S, 4R)-4-methylglutamic acid (SYM 2081, 1 microM), which selectively desensitizes KA receptors. 4. The antidromic population spike of dentate granule cells evoked by stimulation of mossy fibres was increased by application of 0.2 microM KA to 160 +/- 10 % of control (n = 6). Whole-cell current-clamp recordings revealed that the stimulus threshold for generating antidromic spikes recorded from a single granule cell was lowered by KA application. 5. Application of KA (0.2 microM) suppressed presynaptic Ca2+ influx to 78 +/- 4 % of control (n = 6), whereas the amplitude of the presynaptic volley was increased. 6. KA at 0.2 microM reversibly suppressed excitatory postsynaptic currents (EPSCs) evoked by mossy fibre simulation to 38 +/- 9 % of control (n = 5). 7. These results suggest that KA receptor activation enhances the excitability of mossy fibres, probably via axonal depolarization, and reduces action potential-induced Ca2+ influx, thereby inhibiting mossy fibre EPSCs presynaptically. This novel presynaptic inhibitory action of KA at the mossy fibre-CA3 synapse may regulate the excitability of highly interconnected CA3 networks.

Animals↗
PubMed1991

Kindling-induced potentiation of excitatory and inhibitory inputs to hippocampal dentate granule cells. II. Effects of the NMDA antagonist MK-801.

The effect of the non-competitive N-methyl-D-aspartate antagonist MK-801 on the early development of kindling-induced potentiation was examined in the rabbit hippocampal dentate gyrus. MK-801 (0.5 mg/kg) was administered 2 h before each daily kindling stimulation was applied to the perforant path. This treatment continued for the first 10 days of kindling. MK-801 depressed the growth of the afterdischarge duration and suppressed development of behavioral seizures. MK-801 did not block kindling-induced potentiation of either the perforant path-dentate granule cell population spike or excitatory postsynaptic potential. Random impulse train stimulation and non-linear systems analytic techniques were used to examine kindling-induced potentiation of presumed GABAergic recurrent inhibitory circuits. Both the magnitude and duration of kindling-induced response inhibition, to the second of each pair of impulses within the train, were reduced in rabbits pretreated with MK-801. These results suggest that MK-801 differentially affects kindling-induced potentiation of excitatory and inhibitory circuits within the rabbit hippocampal dentate gyrus.

Analysis of Variance↗
PubMed1992

Pre- and postsynaptic inhibition by opioids in rat striatum.

The physiological role of opioid peptides in the rat striatum was sought by intracellular recording in vitro. Excitatory synaptic potentials (mediated by glutamate or aspartate) and inhibitory synaptic potentials (mediated by GABA) were isolated pharmacologically and/or by positioning the stimulation electrode over the external capsule. Opioid agonists and antagonists selective for mu-, delta-, and kappa-receptors were applied by superfusion. Two main actions of opioids were observed. First, mu- and delta-selective opioids presynaptically inhibited the excitatory postsynaptic potential, whereas only delta-selective opioids decreased the inhibitory synaptic potential. Second, a small subpopulation of cells (not medium spiny neurons) were hyperpolarized by delta-selective agonists. The results indicate that the main action of opioids on striatal neurons is presynaptic inhibition of the corticostriate excitatory synaptic input.

Action Potentials↗