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PubMed1997

A nonrandom dynamic component in the synaptic noise of a central neuron.

Continuous segments of synaptic noise were recorded in vivo from teleost Mauthner cells and were studied with the methods of nonlinear analysis. As in many central neurons, this ongoing activity is dominated by consecutive inhibitory postsynaptic potentials. Recurrence plots and first or third order Poincaré maps combined with surrogate shuffling revealed nonrandom patterns consistent with the notion that synaptic noise is a continuously varying mixture of periodic and chaotic phases. Chaos was further demonstrated by the occurrence of unstable periodic orbits. The nonrandom component of the noise is reproducibly and persistently reduced when the level of background sound, a natural stimulus for networks afferent to the Mauthner cell, is briefly elevated. These data are consistent with a model involving a reciprocally connected inhibitory network, presynaptic to the Mauthner cell and its intrinsic properties. The presence of chaos in the inhibitory synaptic noise that regulates the excitability of the Mauthner cell and its sensitivity to external stimuli suggests that it modulates this neuron's function, namely to trigger a fast escape motor reaction following unexpected sensory information.

Acoustic Stimulation↗

PubMed1987

Cholinergic excitatory synaptic potentials of neurones in mammalian lumbar paravertebral ganglia.

Synaptic potentials and the electrophysiological properties of 201 cells in the 4th lumbar paravertebral ganglia of the rabbit were studied in vitro using intracellular electrophysiological recording techniques. Cells had a mean transmembrane potential of 55.1 +/- 0.8 mV, a mean input resistance of 37.0 +/- 6.6 M omega (range 29.9-61.1) and a mean membrane time constant of 6.0 +/- 0.6 ms. Synaptic potentials in ganglionic neurones were evoked by electrical stimulation of the rami communicantes, inferior lumbar splanchnic nerves and the paravertebral chain from segments both above and below the L4 ganglion. Synaptic responses consisted of a fast, hexamethonium-sensitive component and, following short periods of higher frequency stimulation, a slow, long lasting, pirenzepine and atropine-sensitive depolarization (slow-EPSP). No phenomenon corresponding to a late slow-EPSP was observed and, under our recording conditions no cells exhibited non-cholinergic slow excitatory or slow inhibitory postsynaptic potentials. It is concluded that fast excitatory synaptic events were mediated by nicotinic receptors whereas slow excitatory synaptic events were mediated by muscarinic m1 receptors. McNeil-A-343, a muscarinic agonist, produced membrane depolarization, a decrease in membrane input conductance and in some cells a repetitive discharge of action potentials. In 60% of cells tested substance P produced a depolarization of the membrane potential with an associated decrease in membrane input conductance.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗

PubMed1987

The role of Renshaw cells in locomotion: antagonism of their excitation from motor axon collaterals with intravenous mecamylamine.

The contribution of Renshaw cell (RC) activity to the production of fictive locomotion in the mesencephalic preparation was examined using the nicotinic antagonist mecamylamine (MEC). After the i.v. administration of 3 doses of MEC (1.0 mg/kg) the following observations were made: 1) ventral root (VR) evoked discharge of RCs was decreased by up to 87.7%, 2) recurrent inhibitory postsynaptic potentials recorded in alpha motoneurons were greatly reduced or abolished, and 3) the rhythmic firing of RCs during the fictive step cycle was abolished in 83% of the cells examined. Locomotor drive potentials (LDPs) in motoneurons persisted during the fictive step cycle after MEC administration. Bursts of motoneuron firing during each fictive step cycle were characterized by increased frequency and number of spikes after MEC, although the burst duration was unaltered for similar step cycle lengths. A greater number and frequency of spikes per burst was also observed in Ia inhibitory interneurons (IaINs), which remained rhythmically active after MEC administration. It is concluded that Renshaw cells are not an integral part of the spinal central pattern generator for locomotion, nor do they control the timing of the motoneuron or IaIN bursts of firing during fictive locomotion. The data are consistent with a role for RCs in limiting the firing rates of motoneurons and IaINs during each burst.

Animals↗

PubMed1982

Intracellular electrophysiology of mammalian peptidergic neurons in rat hypothalamic slices.

The magnocellular neuropeptidergic cells (MNCs) of the paraventricular and supraoptic nuclei have been a model for biochemical and physiological studies of peptidergic neurons in the mammalian brain, but nearly all the electrophysiological studies of these vasopressinergic and oxytocinergic neuroendocrine cells are based on extracellular recordings. This paper reviews recent literature on electrophysiological properties of neurons in the magnocellular nuclei in which the rat in vitro slice preparation and intracellular recording were used. Spontaneously occurring action potentials and synaptic potentials (excitatory and inhibitory) have been observed in hypothalamic slices. The spike patterns have included slow and irregular firing, short rapid bursts of inactivating spikes, and slow phasic discharge with prolonged active and silent periods. Some studies have shown that increased osmolality causes neuronal firing, but this area is controversial. Intracellular injections of lucifer yellow have shown that some MNCs are dye-coupled and electron microscopic observations with the freeze-fracture technique have revealed occasional gap junctions, thus suggesting that some MNCs are electrotonically coupled. Both excitatory and inhibitory postsynaptic potentials have been evoked with extracellular stimulation. Therefore, action potentials, synaptic potentials, burst discharges, and probably electrotonic coupling have been found with intracellular recording in mammalian neuroendocrine cells. Future studies with intracellular recording and staining followed by immunohistochemical identification of cells should provide significant new information on the membrane physiology and synaptic pharmacology of vasopressinergic and oxytocinergic cells.

Action Potentials↗

PubMed1991

Commissural responses of rat retrohippocampal neurons.

Synaptic responses of commissurally activated rat subicular and entorhinal neurons were studied intracellularly in vivo by stimulating the contralateral dentate gyrus. The most prominent synaptic responses in both subicular and entorhinal neurons were inhibitory postsynaptic potentials (IPSPs). IPSPs were generated in combination with antidromic spikes and/or excitatory postsynaptic potentials (EPSPs) and orthodromic spikes. No dependency between any two response types were found. Commissurally projecting subicular neurons (identified by the presence of antidromic spikes evoked by contralateral stimulation) were found, extending previous anatomical studies. Commissurally projecting entorhinal neurons were found in layer II, confirming previous anatomical studies. Positive correlations between antidromic spike latency and depth of recording sites supported the interpretation that axons projected along the fiber bundles of the hippocampal commissures and angular bundle to distribute to their targets. Possible circuits that could have mediated the excitatory and inhibitory responses of these retrohippocampal neurons are considered.

Animals↗

PubMed1996

Developmental down-regulation of LTD in cortical layer IV and its independence of modulation by inhibition.

For in vitro LTD to remain viable as a model for synaptic weakening in visual cortical plasticity, it is crucial that it display a critical period for its induction within layer IV. A complicating factor, however, is that LTD in layer IV is modulated by inhibitory postsynaptic potentials (IPSPs); postsynaptic responses characterized as containing IPSPs do not depress in response to 1 Hz afferent stimulation. By blocking IPSPs intracellularly, we find that the ability to induce LTD in layer IV neurons is restored in juvenile, but not in mature animals. This developmental down-regulation of LTD induction is specific for layer IV when compared with LTD induction in layers II/III. These data are consistent with the hypothesis that an LTD-like phenomenon is involved in critical period plasticity and is apparently independent of developmental changes in inhibitory circuitry.

Animals↗

PubMed1995

Phosphinic acid analogues of GABA. 2. Selective, orally active GABAB antagonists.

In 1987, 25 years after the synthesis of the potent and selective GABAB agonist baclofen (1), Kerr et al. described the first GABAB antagonist phaclofen 2. However, phaclofen and structurally similar derivatives 3-5 did not cross the blood-brain barrier and hence were inactive in vivo as central nervous system agents. As a consequence, the therapeutic potential of GABAB antagonists remained unclear. In exploring GABA and baclofen derivatives by replacing the carboxylic acid residue with various phosphinic acid groups, we discovered more potent and water soluble GABAB antagonists. Electrophysiological experiments in vivo demonstrated that some of the new compounds were capable of penetrating the blood-brain barrier after oral administration. Neurotransmitter release experiments showed that they interacted with several presynaptic GABAB receptor subtypes, enhancing the release of GABA, glutamate, aspartate, and somatostatin. The new GABAB antagonists interacted also with postsynaptic GABAB receptors, as they blocked late inhibitory postsynaptic potentials. They facilitated the induction of long-term potentiation in vitro and in vivo, suggesting potential cognition enhancing effects. Fifteen compounds were investigated in various memory and learning paradigms in rodents. Although several compounds were found to be active, only 10 reversed the age-related deficits of old rats in a multiple-trial one-way active avoidance test after chronic treatment. The cognition facilitating effects of 10 were confirmed in learning experiments in Rhesus monkeys. The novel GABAB antagonists showed also protective effects in various animal models of absence epilepsy.

Administration, Oral↗

PubMed2000

Nicotine reverses GABAergic inhibition of long-term potentiation induction in the hippocampal CA1 region.

Nicotine is known to enhance cognitive function but the mechanism is unknown. The present study examined the modulatory effect of nicotine on the induction of long-term potentiation (LTP), a synaptic model of learning and memory. A weak tetanic stimulation consisting of 20 pulses at 100 Hz induced stable LTP in the hippocampal CA1. The induction of LTP was completely blocked if the tetanus was delivered in the presence of muscimol (2.5 microM), a gamma-aminobutyric acid (GABA) receptor agonist. This inhibition was sensitive to, and reversed by, not only nicotinic acetylcholine receptor (nAChR) agonists (nicotine and epibatidine), but also the alpha7 nAChR-selective antagonist methyllycaconitine (MLA). Furthermore, ACh-puff activation of alpha7 nAChRs on feedforward interneurons induced inhibitory postsynaptic currents in pyramidal cells that were blocked by nicotine or MLA. In addition, nicotine reduced field monosynaptic inhibitory postsynaptic potentials in the presence of MLA. These results suggest not only two pathways of nicotine-induced disinhibition of pyramidal cells, one involving desensitization of alpha7 nAChRs and the other involving non-alpha7 nAChRs, but also two potential mechanisms underlying the modulatory effect of nicotine on LTP induction, both reducing GABAergic inhibition, thereby indirectly increasing the excitability of pyramidal cells.

Aconitine↗

PubMed1985

Modulation of inhibition in the hippocampus in vivo.

The nature and mechanisms of septohippocampal transmission have been elucidated by taking advantage of an in situ preparation in experiments with Sprague-Dawley rats under urethane. Both extracellular field potentials and intracellular recordings were made in CA1-3 regions of the hippocampus; and the hippocampal commissure and medial septum stimulated to evoke synaptic activity. Using muscarinic and nicotinic agonists and antagonists it was shown that both acetylcholine and medial septal activity can increase the excitability of pyramidal cells, mainly through muscarinic receptors. The effect of septal stimulation was enhanced by local application of physostigmine and reduced by intraventricular injections of hemicholinium. It was also shown that acetylcholine, when applied in the stratum pyramidale, can reduce the voltage and conductance changes observed during evoked inhibitory postsynaptic potentials (IPSP) without affecting the action of gamma-aminobutyric acid on membrane conductance and voltage. It is therefore proposed that acetylcholine can reduce evoked IPSPs through presynaptic inhibition. Evidence is also presented that medial septal stimulation can reduce the efficacy of evoked IPSPs. These observations provide further support for the existence of a cholinergic septohippocampal pathway.

Acetylcholine↗

PubMed1996

Neuronal diversity in the subiculum: correlations with the effects of somatostatin on intrinsic properties and on GABA-mediated IPSPs in vitro.

1. We used intracellular current-clamp techniques to record from 33 ventral subicular neurons in slices or rat hippocampal formation. Presumed pyramidal neurons were characterized by their responses to depolarizing current pulses as either intrinsically burst firing (IB) or regular spiking (RS). Within the subiculum, IB cells were encountered most frequently in the deep cell layer, whereas RS cells were encountered most frequently in the superficial cell layer. IB cells had more depolarized resting potentials, lower input resistances, and more sag in their voltage responses to hyperpolarizing current pulses. 2. Somatostatin (5 microM) applied in the bathing medium caused a hyperpolarization and reduction in input resistance. These effects were of greater magnitude in IB cells. Somatostatin had no effect on sag in either cell type. These effects of somatostatin were unchanged in the presence of gamma-aminobutyric acid (GABA) receptor antagonists. 3. In a series of experiments conducted in RS cells only, somatostatin reduced the amplitude of the late but not the early component of evoked biphasic inhibitory postsynaptic potentials (IPSPs). 4. A second series of experiments was conducted in RS and IB cells. Somatostatin reduced the amplitude of pharmacologically isolated GABAA IPSPS in both cell types. In IB cells but not RS cells there was a correlation between this effect and the somatostatin-induced hyperpolarization. Somatostatin also reduced the amplitude of isolated GABAB IPSPS in both cell types, but more so in IB cells. 5. Somatostatin had no effect on the reversal potential of either IPSP in either cell type and no effect on the GABAA-mediated conductance in either cell type. In contrast, the GABAB-mediated conductance was reduced, especially in IB cells. 6. The effects of somatostatin on GABAA IPSPS are principally a result of membrane shunting and reductions in ionic driving force, but these mechanisms do not account for the reduction in GABAB IPSPS. 7. We suggest that the combined effects of somatostatin are likely to alter the balance between fast and slow inhibition and to do so more in IB cells than in RS cells.

Animals↗

PubMedDate not supplied

Serotonin and local circuits in rat hippocampus.

Serotonin produces several actions in rat hippocampal neurons recorded in an in vitro slice preparation. These include activation of a voltage-independent potassium current which results in the hyperpolarization of the recorded cells, the blockage of a calcium-dependent slow potassium current underlying the slow after-hyperpolarization (AHP) which follows a burst firing and generation of a slow late depolarization associated with the blockage of a persistent potassium current. An additional effect that we detected recently involves a blockage of inhibitory postsynaptic potentials (IPSP), primarily the slow IPSP, likely to be mediated by activation of potassium currents through a gamma-aminobutyric acid (GABA)-B receptor. The reduction in the IPSPs is produced by a lower concentration of serotonin than that required to produce the hyperpolarization. The lack of reduced sensitivity to GABA indicates that the effect of serotonin on the IPSPs might be presynaptic. Indeed, serotonin has a much larger effect on putative interneurons than on pyramidal neurons. It is suggested that serotonin can enhance reactivity of the hippocampus to afferent stimulation by reducing slow inhibitory synaptic potentials while at the same time reducing the spontaneous activity of the recorded neurons. These effects of serotonin develop relatively late (2-3 weeks postnatally), along with the late appearance of the slow inhibitory potentials.

Animals↗

PubMed1996

Effects on iontophoretically applied acetylcholine on membrane potential and synaptic activity of bulbar respiratory neurones in decerebrate cats.

Intracellular recordings were made from bulbar respiratory neurones of decerebrate cats, together with iontophoretic application of acetylcholine and its specific antagonists to assess cholinergic mechanisms involved in the central respiratory network in vivo. Of 126 respiratory-related neurones impaled in the ventral respiratory group, iontophoresis of acetylcholine produced depolarization in 67 cells (53%), hyperpolarization in 36 cells (29%), and no effect in the remaining 23 cells (18%). Depolarization occurred predominantly in laryngeal motoneurones (31/40) and bulbo-spinal neurones (4/5), while a comparable number of non-antidromically-activated respiratory neurones displayed either depolarization (33/81) or hyperpolarization (31/81). Acetylcholine had no significant effect on excitatory and inhibitory postsynaptic potentials in all types of neurones tested. Both depolarizing effects of acetylcholine were antagonized by co-iontophoresis of atropine, but not by hexamethonium. Input resistance was increased (7/9) or unchanged (2/9) in depolarized cells, whereas it was unaltered in all hyperpolarized cells tested (n = 6). The present results suggest that the distribution and functions of cholinergic muscarinic receptors are different for the laryngeal and bulbo-spinal types of respiratory neurones and the non-antidromically-activated respiratory neurones in the cat.

Acetylcholine↗

PubMed1999

Cholinergic induction of theta-frequency oscillations in hippocampal inhibitory interneurons and pacing of pyramidal cell firing.

Cholinergic and GABAergic medial septal afferents contribute to hippocampal theta activity in part by actions on local interneurons. Interneurons near the border between stratum radiatum and stratum lacunosum-moleculare (LM) display intrinsic membrane potential oscillations at theta frequency when depolarized near threshold. First, whole-cell current-clamp recordings in rat hippocampal slices were used to examine effects of the cholinergic agonist carbachol on biocytin-labeled LM interneurons. At resting membrane potential, cells were depolarized by bath application of 25 microM carbachol, and the depolarization was sufficient to induce membrane potential oscillations (2.4 +/- 0.2 mV) that paced cell firing. Carbachol also depolarized LM interneurons in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione, (+/-)-2-amino-5-phosphonopentanoic acid, and bicuculline, indicating that cholinergic depolarization of LM cells does not depend on ionotropic glutamate or GABA(A) synaptic transmission in local circuits. Atropine blocked the depolarization, indicating that muscarinic receptors were involved. Minimal stimulation applied to visually identified LM interneurons was then used to determine if spontaneous activity in CA1 pyramidal cells can be paced by rhythmic inhibition generated by LM cells at theta frequency. Inhibitory postsynaptic potentials evoked in pyramidal cells by single minimal stimulations were followed by rebound depolarizations and action potentials. When trains of minimal stimulation were delivered, membrane potential oscillations of depolarized pyramidal cells followed the stimulation frequency. Minimal stimulation led pyramidal cell firing with an average phase of 177 degrees. Thus, muscarinic induction of theta-frequency membrane potential oscillations in LM interneurons may contribute to the generation of rhythmic inhibition that paces intrinsically generated theta activity in CA1 pyramidal cells.

2-Amino-5-phosphonovalerate↗

PubMed1995

Inhibition in the superior olivary complex: pharmacological evidence from mouse brain slice.

1. The effects of gamma-aminobutyric acid (GABA) and glycine and their respective antagonists were determined for neurons in the mouse superior olivary complex. Brain slices (400 microns) were cut in the frontal plane and maintained in an oxygenated saline solution for physiological recording. Recordings were made from neurons in the lateral superior olive (LSO) or medial nucleus of the trapezoid body (MNTB) with glass micropipettes filled with 4 M potassium acetate. 2. Ipsilateral and contralateral synaptic responses were elicited by applying current pulses to the trapezoid body through bipolar stimulating electrodes located at positions lateral and medial to the olivary complex. Both intracellular and extracellular recordings were studied before, during, and after application of drugs to the saline bath containing the tissue slice. 3. Intracellular recordings from 10 neurons in LSO showed that GABA (1-10 mM) caused a concentration-dependent drop in membrane resistance and either reduced or blocked postsynaptic excitatory responses. Similar effects were found in five cells tested with glycine (1-10 mM). Three neurons tested with both GABA and glycine were affected by both drugs. Extracellular spikes were blocked in 53 out of 67 LSO neurons tested with GABA and 29 out of 35 neurons tested with glycine. Seventeen out of 23 neurons tested with both GABA and glycine were affected by both. 4. GABA had a powerful blocking effect on extracellularly recorded action potentials evoked by current-pulse stimulation of the trapezoid body in seven LSO neurons tested after adding the glycine receptor antagonist, strychnine (1 microM), to the bath. GABA also lowered the membrane resistance of one LSO neuron in which intracellular recordings were made in the presence of strychnine. 5. Neurons in MNTB also were affected by GABA and glycine but the proportion of sensitive cells was less than in LSO. GABA reduced membrane resistance in 6 out of 16 neurons and glycine produced a similar effect in 14 out of 26 neurons from which intracellular recordings were made. Six out of 14 neurons tested with GABA and glycine responded to both. Extracellular spikes were eliminated or reduced in amplitude by GABA in 15 out of 44 cells and by glycine in 40 out of 68 cells tested. Eleven out of 29 cells from which extracellular recordings were made were affected by both. 6. The glycine antagonist, strychnine (0.25 - 1.0 muM), blocked both ipsilateral and contralateral inhibitory postsynaptic potentials (IPSPs) in LSO.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1990

Paired-pulse depression of monosynaptic GABA-mediated inhibitory postsynaptic responses in rat hippocampus.

1. Intracellular recording techniques were used to characterize monosynaptic inhibitory postsynaptic potentials (IPSPs) and currents (IPSCs) in rat hippocampal slices and to study the mechanism of paired-pulse depression of these synaptic responses. This was achieved by stimulation in stratum radiatum close (less than 0.5 mm) to an intracellularly recorded CA1 neurone after pharmacological blockade of all excitatory synaptic transmission. 2. Under these conditions, low-frequency stimulation (0.033 Hz) evoked a pure biphasic IPSP, which had a short and constant latency to onset. This IPSP was blocked by tetrodotoxin (1 microM) suggesting that it resulted from the electrical stimulation of the axons and/or cell bodies of a monosynaptic inhibitory pathway. 3. Picrotoxin (100 microM) abolished the early component of the biphasic IPSP/C. It left an intact, pure late IPSP/C (IPSP/CB) which had a latency to onset of 29 +/- 2 ms, latency to peak of 139 +/- 4 ms, a duration of 723 +/- 135 (range 390-1730) ms and a reversal potential of -93 +/- 2 mV. The duration was highly dependent on the stimulus intensity whereas the latency to onset was largely independent of the stimulus intensity. The IPSP/CB was reduced or abolished by 1 mM-phaclofen. 4. Phaclofen (1 mM) and 2-hydroxy-saclofen (0.1-1.0 mM) reversibly depressed (60-100%) the late component of the biphasic IPSP/C and, where maximally effective, left a pure, early IPSP/C (IPSP/CA). The IPSP/CA had a latency to onset of 3 ms or less, a latency to peak of 17 +/- 1 ms, a duration of 225 +/- 3 ms and a reversal potential of -75 +/- 2 mV. 5. Two shocks of identical strength were applied in close succession to characterize, and to study the mechanisms underlying, frequency-dependent depression of inhibitory synaptic responses. Paired-pulse depression was seen for both phases of the biphasic IPSP/C and of the pure IPSP/CB, recorded in the presence of picrotoxin. Paired-pulse depression was not accompanied by changes in the reversal potential of either component, indicating that it was caused by a reduction in the two synaptic conductances. Paired-pulse depression was greater when high stimulus intensities were employed. 6. Paired stimuli were applied at separation intervals of between 5 ms and 10 s to determine the temporal profile of frequency-dependent depression. Paired-pulse depression of both IPSCA and IPSCB was most pronounced at an interstimulus interval of 100-125 ms and ceased to occur at intervals greater than 5 10s.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed1988

Information processed by dorsal horn spinocerebellar tract neurones in the cat.

1. A group of spinocerebellar tract neurones located in the dorsal horn of the mid-lumbar segments of the spinal cord but outside of Clarke's column have been investigated by intracellular and extracellular recording from their somata. The existence of these neurones has been demonstrated previously using anatomical methods, but their properties have not been investigated in detail. In contrast to the cells of Clarke's column, these neurones were found to process information from both exteroceptors and proprioceptors. 2. All of the investigated neurones were powerfully excited following stimulation of muscle nerves at strengths sufficient to activate group II afferents while there was no evidence for actions from group I afferents onto any of them. Most were excited by group II afferents from many different nerves, including those from muscles acting on different joints. The latencies and properties of the excitatory postsynaptic potentials (EPSPs) suggest that at least a large proportion of them were monosynaptically evoked. 3. All of the neurones were powerfully excited following electrical stimulation of cutaneous afferents. The most potent effects were evoked from the saphenous and sural nerves which innervate the skin of the leg and thigh. In many cases these EPSPs had latencies indicative of a monosynaptic connection. The superficial peroneal and tibial nerves which innervate the skin of the foot evoked EPSPs which were usually smaller and of longer latency. 4. Responses to adequate stimulation of cutaneous afferents were examined in twenty extracellularly recorded neurones. All but one of them could be discharged by weak mechanical stimulation of the skin over the proximal part of the leg and thigh. None were activated from the skin of the foot. 5. Some of the neurones were influenced by stimulation of the posterior knee joint or interosseous nerves. These actions were relatively weak, however, suggesting that the powerful effects seen on stimulation of muscle nerves were unlikely to have been mediated by articular or Pacinian afferents which contaminate them. 6. Excitation from group II afferents was sometimes followed by inhibition (in 27% of the neurones). In almost all cases the inhibitory postsynaptic potentials (IPSPs) were evoked from the same nerves which evoked EPSPs. The minimal latencies of the IPSPs were approximately 1.0 ms longer than those of the EPSPs, suggesting that they were evoked disynaptically. 7. The possibility that these neurones provide information regarding limb position is discussed.

Action Potentials↗

PubMed2002

Effects of the anticonvulsant retigabine on cultured cortical neurons: changes in electroresponsive properties and synaptic transmission.

The whole-cell patch-clamp technique was used to examine the effects of retigabine, a novel anticonvulsant drug, on the electroresponsive properties of individual neurons as well as on neurotransmission between monosynaptically connected pairs of cultured mouse cortical neurons. Consistent with its known action on potassium channels, retigabine significantly hyperpolarized the resting membrane potentials of the neurons, decreased input resistance, and decreased the number of action potentials generated by direct current injection. In addition, retigabine potentiated inhibitory postsynaptic currents (IPSCs) mediated by activation of gamma-aminobutyric acid(A) (GABA(A)) receptors. IPSC peak amplitude, 90-to-10% decay time, weighted decay time constant, slow decay time constant, and, consequently, the total charge transfer were all significantly enhanced by retigabine in a dose-dependent manner. This effect was limited to IPSCs; retigabine had no significant effect on excitatory postsynaptic currents (EPSCs) mediated by activation of non-N-methyl-D-aspartate ionotropic glutamate receptors. A form of short-term presynaptic plasticity, paired-pulse depression, was not altered by retigabine, suggesting that its effect on IPSCs is primarily postsynaptic. Consistent with the hypothesis that retigabine increases inhibitory neurotransmission via a direct action on the GABA(A) receptor, the peak amplitudes, 90-to-10% decay times, and total charge transfer of spontaneous miniature IPSCs were also significantly increased. Therefore, retigabine potently reduces excitability in neural circuits via a synergistic combination of mechanisms.

Animals↗

PubMed1990

The Involvement of N-Methyl-D-Aspartate Receptors in Induction and Maintenance of Long-Term Potentiation in Rat Visual Cortex.

Pyramidal neurons from layers II and III of rat visual cortex slices were studied with intracellular recordings. The involvement of N-methyl-D-aspartate (NMDA) receptors was investigated: (1) in the synaptic response to white matter stimulation; (2) in the induction of long-term potentiation (LTP); and (3) in the maintenance of LTP. Bath application of 25 microM of 2-amino-5-phosphonovalerate (APV), an NMDA receptor antagonist, caused a slight (< 10%) reduction of the amplitude of the synaptic response elicited by white matter stimulation. The APV-sensitive excitatory postsynaptic potential (EPSP) had a longer peak latency and duration than the APV-resistant EPSP. Bath application of 10 microM of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA glutamate receptor antagonist, revealed a CNQX-resistant EPSP in response to white matter stimulation which was APV-sensitive. The time course of the CNQX-resistant EPSP was similar to that of the APV-sensitive EPSP and its onset latency was similar to that of the synaptic response in normal medium. Bath application of the GABA-A antagonist bicuculline (0.1 to 0.5 microM) led to a progressive enhancement of the amplitude of the APV-sensitive EPSP. At bicuculline concentrations above 0.3 microM the amplitude of this EPSP increased with membrane depolarization as was the case for the CNQX-resistant EPSP implying that the NMDA receptors were located on the recorded neuron. The susceptibility of the cells to undergo LTP was tested at various concentrations of bicuculline. The effectiveness of bicuculline treatment was quantified by comparing the amplitudes of the synaptic response to just subthreshold stimuli at two post-stimulus delays: (i) at 22 ms, which corresponds to the time to peak of both the initial inhibitory postsynaptic potential and the APV-sensitive EPSP; and (ii) at 8 - 11 ms post-stimulus, which corresponds to the peak of the postsynaptic potential (PSP) in normal medium. Bath application of APV, 20 min after the conditioning tetanus, allowed the authors to measure the amplitude of the APV-sensitive EPSP in the potentiated response. In normal medium, the ratio of the late over the early PSP amplitude was 33.6 +/- 4.1% and tetanic stimulation failed to induce LTP. The conditions remained the same at bicuculline concentrations of 0.1 to 0.2 microM. At higher concentrations of bicuculline the amplitude ratio of late versus early PSP increased and tetanic stimulation induced LTP. In cells, in which bicuculline had caused small ratio increases, only the APV-sensitive EPSP underwent LTP. In cells in which bicuculline had caused large ratio changes, both the APV-resistant and the APV-sensitive EPSP showed LTP. Together with the previous finding that blockade of NMDA receptors prevents LTP (Artola and Singer, 1987) these results suggest that there is a threshold for LTP induction, which is only reached if NMDA receptor-gated channels are sufficiently activated. The data indicate further that the NMDA receptor-mediated EPSP is itself susceptible to LTP whereby its LTP threshold is lower than that of the APV-resistant EPSP. Given the different LTP thresholds of the APV-resistant and APV-sensitive EPSPs, the possibility is raised that their potentiation depends on different mechanisms.

Journal Article↗