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Y Yaari

Publications and source records attributed to Y Yaari.

At least 19 recordsLinked to original sources
PubMed1991

Patch clamp analysis of excitatory synaptic currents in granule cells of rat hippocampus.

1. Excitatory postsynaptic potentials (EPSPs) and their underlying currents (EPSCs) were recorded from dentate granule cells in thin hippocampal slices of rats using the tight-seal whole-cell recording technique. 2. At resting membrane potentials (ca -60 to -70 mV), the EPSCs clearly consisted of a dominant fast and a smaller slow component. The slow EPSC component markedly increased with depolarization. This resulted in a region of negative slope conductance (between -50 and -30 mV) in the peak current-voltage (I-V) relation of the dual-component EPSC in most neurones. The EPSCs reversed entirely at -1.2 +/- 2.8 mV (n = 15). 3. Using selective antagonists of N-methyl-D-aspartate (NMDA) and non-NMDA excitatory amino acid receptors, two pharmacologically distinct components of the natural EPSCs were isolated. The non-NMDA EPSCs displayed a linear I-V relation. Their rise times (0.5-1.9 ms) were independent of membrane voltage but seemed to depend critically on the precise dendritic location of the synapse. Their decay was approximated by a single exponential with a time constant ranging from 3 to 9 ms. The time course of these EPSCs was independent of changes in extracellular Mg2+. 4. The NMDA EPSCs displayed a non-linear I-V relation. At resting membrane potentials their peak amplitudes were 20 pA and increased steadily with depolarization to -30 mV. At membrane voltages positive to -30 mV the peak I-V relation was linear. The rise times of NMDA EPSCs ranged from 4 to 9 ms and were insensitive to membrane voltage. 5. The NMDA EPSCs decayed biexponentially. Both time constants, tau f and tau s, increased with depolarization in an exponential manner, tau s being more voltage dependent than tau f. Lowering extracellular Mg2+ slightly reduced both rate constants but did not completely abolish their voltage sensitivity. 6. Bath application of NMDA to outside-out patches from granule cells induced single channel currents of 52 pS in nominally Mg(2+)-free solutions. They displayed a burst-like single-channel activity with clusters of bursts lasting several hundreds of milliseconds. Currents through single NMDA receptor channels reversed around 0 mV. 7. The fractional contributions of NMDA and non-NMDA components to peak currents and synaptic charge transfer were assessed. At resting membrane potential the NMDA EPSC component accounted for 23% of the peak current and for 64% of the synaptic charge transfer. The contribution of the NMDA EPSC component to the synaptic charge transfer strongly increased with small depolarizations from rest.

Animals↗
PubMed1990

Voltage sensitivity of NMDA-receptor mediated postsynaptic currents.

Patch-clamp techniques were used to record pharmacologically-isolated N-methyl-D-aspartate-mediated excitatory postsynaptic currents (NMDA-EPSCs) from dentate granule cells in thin rat hippocampal slices. Membrane voltage modulated these EPSCs in two ways. Firstly, depolarization from resting potential enhanced EPSC amplitudes, as expected for a voltage-dependent block by Mg2+ of synaptically activated NMDA receptor channels. Secondly, depolarization markedly prolonged the time course of decay of NMDA-EPSCs in normal and low extracellular Mg2+. Both mechanisms were complementary in establishing a strong dependence between membrane potential and the amount of charge, namely Ca2+, transferred through synaptically activated NMDA receptor channels, that presumably underlies induction of long-term potentiation in the hippocampus.

Animals↗
PubMed1988

The relationship between interictal and ictal paroxysms in an in vitro model of focal hippocampal epilepsy.

In studies of focal epilepsy it is frequently assumed that the interictal spike is the elementary form of epileptic activity and that seizure, or ictal, episodes evolve by temporal summation and spatial expansion of interictal paroxysms. We examined this hypothesis in an in vitro model of acute focal epilepsy produced by perfusing rat hippocampal slices with solutions containing moderately elevated concentrations of K+. Some of the preparations treated in this way displayed recurring electrical seizures in the CA1 field. Each seizure episode typically evolved by a seemingly smooth progression of brief interictal bursts into sustained ictal discharge. However, exposure of preparations showing electrical seizures to blockers of synaptic transmission or to cholinergic agonists abolished interictal spiking in all hippocampal fields but did not impede the initiation of ictal episodes in area CA1. Likewise, severing the connections between areas CA3 and CA1 abolished interictal spiking in area CA1 without disrupting the initiation of seizures in this region. These data clearly show that in this model, focal seizures arise independent of interictal spikes and through different cellular mechanisms. While interictal electrogenesis requires chemical synaptic excitation, ictal episodes can be initiated and maintained by nonsynaptic neuronal interactions.

Animals↗
PubMed1987

Development of two types of calcium channels in cultured mammalian hippocampal neurons.

Calcium influx through voltage-gated membrane channels plays a crucial role in a variety of neuronal processes, including long-term potentiation and epileptogenesis in the mammalian cortex. Recent studies indicate that calcium channels in some cell types are heterogeneous. This heterogeneity has now been shown for calcium channels in mammalian cortical neurons. When dissociated embryonic hippocampal neurons from rat were grown in culture they first had only low voltage-activated, fully inactivating somatic calcium channels. These channels were metabolically stable and conducted calcium better than barium. Appearing later in conjunction with neurite outgrowth and eventually predominating in the dendrites, were high voltage-activated, slowly inactivating calcium channels. These were metabolically labile and more selective to barium than to calcium. Both types of calcium currents were reduced by classical calcium channel antagonists, but the low voltage-activated channels were more strongly blocked by the anticonvulsant drug phenytoin. These findings demonstrate the development and coexistence of two distinct types of calcium channels in mammalian cortical neurons.

Animals↗
PubMed1986

Acetylcholine modulates two types of presynaptic potassium channels in vertebrate motor nerve terminals.

Using external microelectrodes to record local circuit currents from preterminal motor nerve axons, two distinct populations of potassium (K) channels were identified in frog motor nerve terminals: delayed rectifier and calcium-activated K channels. Both are sensitive to the transmitter acetylcholine (ACh) which, when externally applied, blocks them in concentrations in the millimolar range. As this action also is not prevented by nicotinic and muscarinic antagonists, it probably is not mediated by classical cholinergic receptors. This cholinergic sensitivity of presynaptic K channels may account for the hyperexcitability of motor nerve terminals manifested when ACh accumulates in the junctional cleft.

Acetylcholine↗
PubMed1986

Activity-dependent depression of nerve action potential by phenytoin.

The action of the anticonvulsant drug phenytoin was investigated on the responsiveness of isolated amphibian and human nerves to repetitive stimulation. At low frequencies of stimulation (0.5-25 Hz) the drug (at a concentration of 0.1 mM) had no notable effect on the compound nerve action potential. By contrast, at higher rates of stimulation (50-300 Hz), it produced a progressive decrease in amplitude and integral of the compound action potential. This effect was positively correlated with the frequency of nerve activation and was markedly enhanced by elevating the extracellular K+ concentration. Thus, phenytoin induces a use- and frequency-dependent depression of axon conduction, which may contribute to its preferential suppression of the spread of high-frequency seizure discharge in the brain.

Action Potentials↗
PubMed1986

Frequency-dependent action of phenytoin on lamprey spinal axons.

The effect of the antiepileptic drug phenytoin (diphenylhydantoin, DPH) was tested on the conduction of intracellularly recorded action potentials in lamprey giant reticulospinal axons. When the isolated spinal cord was exposed to 80 microM DPH for up to 4 h, no significant effect was seen on the amplitude or conduction velocity of the action potential, although the maximum rate of rise was reduced from 247.8 to 149.6 V/s after 1 h. However, at higher stimulus frequencies both the amplitude and conduction velocity of the action potential were reduced progressively during a 500 stimulus train. The reduction was greater the higher the stimulus frequency, and was reversed upon return to 1 Hz stimulation. At frequencies greater than 40 Hz an all-or-none block developed. This also developed sooner the higher the stimulus frequency. Axons bathed in drug-free solutions did not show this effect at stimulus frequencies up to 100 Hz. Similar effects were seen in 16 microM DPH when the spinal cord was exposed to the drug overnight. This is close to the human therapeutic CSF level. The frequency-dependent depression of the action potential was greatly potentiated by increasing the extracellular potassium concentration from 2.1 to 5 mM. Under these conditions the axons rapidly developed block at stimulus frequencies as low as 2 Hz, and this was not reversible during a 5 h wash. In the absence of DPH, 5 mM potassium produced a 4-5 mV depolarization, but did not induce a frequency-dependent block. This effect of potassium may be important to the therapeutic effect of DPH because during epileptiform activity the extracellular K+ increases several fold.

Action Potentials↗
PubMed1986

Phenytoin: mechanisms of its anticonvulsant action.

Phenytoin is a major anticonvulsant drug that is very effective in controlling a wide variety of seizure disorders while impairing neurological function little, if at all. Early work suggested the hypothesis that the drug's effects were due to a selective block of high-frequency neuronal activity. This theory is reevaluated in the light of accumulated observations on the effects of phenytoin in many neuronal and synaptic preparations. Most of these observations can be explained by a use- and frequency-dependent suppression of the sodium action potential by phenytoin, with a consequent filtering out of sustained high-frequency neuronal discharges and synaptic activity. The molecular mechanism for this is a voltage-dependent blockade of membrane sodium channels responsible for the action potential. Through this action, phenytoin obstructs the positive feedback that underlies the development of maximal seizure activity, while normal brain activity, proceeding at lower neuronal firing rates, is spared its depressant action. Other mechanisms of action that may contribute to the drug's efficacy and selectivity are also discussed.

Action Potentials↗
PubMed1986

Nonsynaptic epileptogenesis in the mammalian hippocampus in vitro. I. Development of seizurelike activity in low extracellular calcium.

Epileptiform activity induced in rat hippocampal slices by lowering extracellular Ca2+ concentration ([Ca2+]o) was studied with extracellular and intracellular recordings. Perfusing the slices with low Ca2+ (less than or equal to 0.2 mM) or EGTA-containing solutions blocked the synaptic responses of hippocampal pyramidal cells (HPCs). Despite the block, spontaneous paroxysms, termed seizurelike events (SLEs), appeared in the CA1 area and then recurred regularly at a stable frequency. Transient hypoxia accelerated their development and increased their frequency. When [Ca2+]o was raised in a stepwise manner, the SLEs disappeared at 0.3 mM. With extracellular recording from the CA1 stratum pyramidale, a SLE was characterized by a large negative shift in the field potential, which lasted for several seconds. During this period a large population of CA1 neurons discharged intensely and often in synchrony, as concluded from the frequent appearance of population spikes. Synchronization, however, was not a necessary precursor for the development of paroxysmal activity, but seemed to be the end result of massive neuronal excitation. The cellular counterpart of a SLE, as revealed by intracellular recording from HPCs in the discharge zone of the paroxysms, was a long-lasting depolarization shift (LDS) of up to 20 mV. This was accompanied by accelerated firing of the neuron. A prolonged after-hyperpolarization succeeded each LDS and arrested cell firing. Brief (approximately 50 ms) bursts were commonly observed before LDS onset. Single electrical stimuli applied focally to the stratum pyramidale or alveus evoked paroxysms identical to the spontaneous SLEs, provided they surpassed a critical threshold intensity. Subthreshold stimuli elicited only small local responses, whereas stimuli of varied suprathreshold intensities evoked the same maximal SLEs. Thus the buildup of a SLE is an all or nothing or a regenerative process, which mobilizes the majority, if not all, of the local neuronal population. Each SLE was followed by absolute and relative refractory periods during which focal stimulation was, respectively, ineffective and less effective in evoking a maximal SLE. In most slices the spontaneous SLEs commenced at a "focus" located in the CA1a subarea (near the subiculum). SLEs evoked by focal stimulation arose near the stimulating electrode. From their site of origin the paroxysmal discharges spread transversely through the entire CA1 area at a mean velocity of 1.74 mm/s. Consequently, the discharge zone of a SLE could encompass for several seconds the entire CA1 area.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1986

Nonsynaptic epileptogenesis in the mammalian hippocampus in vitro. II. Role of extracellular potassium.

The role of extracellular K+ (K+o) in nonsynaptic epileptogenesis induced in the CA1 area of rat hippocampal slices by lowering [Ca2]o was studied with K+-selective microelectrodes (KSMs). Extracellular field potentials and [K+]o were recorded simultaneously with 1-2 KSMs in the CA1 stratum pyramidale. In slices perfused with an oxygenated standard physiological solution (containing 2 mM Ca2+), base-line [K+]o was stable for several hours. The washout of Ca2+o was accompanied by a gradual tonic rise of [K+]o. Spontaneous and stimulus-evoked maximal seizurelike events (SLEs) appeared when [K+]o was approximately 0.5 mM above the initial 5 mM base line. These changes were reversible in normal medium. When K+o was pressure ejected in the CA1 stratum pyramidale of spontaneously active slices, a local rise in [K+]o of approximately 0.5 mM was necessary to trigger a SLE. A similar apparent [K+]o "threshold" was associated with SLEs evoked by electrical stimulation. Increasing [K+] in the perfusing solution by small increments (1 mM) markedly enhanced SLEs frequency and velocity of spread and decreased the period of absolute refractoriness that succeeded each paroxysm. Similar changes occurred during periods of transient hypoxia. Small [K+] decreases in the perfusate had the converse effects. Spontaneous SLEs were associated with phasic increases in [K+]o. In simultaneous [K+]o recordings from two layers, these transients were largest (up to 3.5 mM above base line) and rose more steeply at the stratum pyramidale. Toward the outer dendritic layers they became smaller, slower in time course, and delayed in onset. We conclude that the main source for these [K+]o transients are the hippocampal pyramidal cell bodies, which discharge intensely during a SLE, and that excess K+o is spatially dispersed around the discharge zone of the paroxysm. [K+]o continued to rise, though at a slower rate, throughout the course of a SLE. Following SLE termination, [K+]o decayed slowly to base line. The invasion of a CA1 region by a propagating SLE was preceded quite often by a slow rise in [K+]o. A sudden transition to a steeply rising [K+]o marked the explosive recruitment of this region into the discharge zone of the spreading paroxysm. The total (tonic and phasic) increase in [K+]o during SLEs did not surpass a maximal level of approximately 9 mM, which was the ceiling level of [K+]o in low [Ca2+]o. However, when spreading depression occurred, [K+]o rose up to 30-40 mM for several minutes. Spreading depression rarely appeared spontaneously despite the recurrence of SLEs, but could be provoked by repetitive electrical stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1985

Frequency-dependent effects of phenytoin on frog junctional transmission: presynaptic mechanisms.

The action of the antiepileptic drug, phenytoin, on junctional transmission at various frequencies of synaptic activation was studied in frog nerve-muscle preparation. Intracellular recordings were made from muscle end-plates, and extracellular focal and subsendothelial recordings were obtained from motor nerve terminals and their parent axons, respectively. When the motor nerve was stimulated at 100-200 Hz, exposure to the drug (0.1-0.3 mM) induced intermittent failures of junctional transmission which appeared faster as the rate of stimulation was increased. At these and at lower stimulation frequencies (30-50 Hz), in which failures of transmission occurred only rarely, phenytoin markedly limited the buildup of end-plate potential amplitude during the period of repetitive nerve stimulation (tetanic potentiation). Several lines of evidence suggest that both drug effects are consequent to a frequency-dependent depression of the action potential at motor axons and terminals, which could lead to an intermittent conduction block at the higher rates of stimulation. The selective action of phenytoin on high frequency synaptic transmission may contribute to the specificity shown by this drug in suppressing epileptic seizures while sparing neuronal activity.

Animals↗
PubMed1985

Suppression by phenytoin of convulsant-induced afterdischarges at presynaptic nerve terminals.

The mechanisms underlying the induction of afterdischarges at presynaptic nerve terminals by convulsant aminopyridines and their suppression by the anticonvulsant drug phenytoin were studied at the frog neuromuscular preparation. Addition of aminopyridine to the perfusing solution induced the appearance of afterdischarges in motor nerve fibres following their primary response to a single nerve stimulus. The afterdischarges seemed to originate at or near the nerve terminals and to propagate both antidromically and orthodromically. The latter resulted in repetitive activation of the neuromuscular synapse. Focal recordings of nerve terminal potentials suggested that aminopyridines may induce afterdischarges by slowing spike repolarization and thereby producing a prolonged depolarization of nerve terminals. Phenytoin suppressed the aminopyridine-induced afterdischarges and the resultant repetitive excitation of the postsynaptic muscle fibres. This effect of phenytoin was associated with a depression of the action potential at the motor nerve terminals but not at their parent axons. These results single the presynaptic nerve terminals as preferential sites for convulsant and anticonvulsant actions.

4-Aminopyridine↗
PubMed1985

Phenytoin suppresses spontaneous ectopic discharge in rat sciatic nerve neuromas.

Afferent fibers ending in nerve-end neuromas generate spontaneous impulse discharge which has been implicated as a cause of paraesthesias and pain following peripheral nerve injury in man. We now show in rats that the anticonvulsant drug phenytoin (PT), applied systemically or topically onto desheathed neuromas, suppresses the generation of neuroma discharge without blocking impulse conduction. The effect is dose-dependent and reversible upon drug washout. Since PT is known to provide effective pain relief in some kinds of neuralgia, the data suggest that the clinical analgesic action of PT in these conditions may, at least in part, involve a direct suppression of ectopic impulses generated in the region of the nerve damage.

Animals↗