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J L Stringer

Publications and source records attributed to J L Stringer.

67 records · Page 4Linked to original sources
PubMed1988

NMDA receptor dependent paroxysmal discharges in the dentate gyrus.

The N-methyl-D-aspartic acid subclass of glutamate receptors is thought to be involved in events that depend on repetitive activation of neurons. The present study shows that repetitive stimulation of CA3 can produce epileptiform discharges in the contralateral dentate gyrus. This distinctive paroxysmal response was blocked by the NMDA antagonists, ketamine and MK-801. The MK-801 blockade required previous activation of the dentate gyrus in the presence of the drug, thus demonstrating, in vivo, a use-dependent effect. These studies show that repetitive, low intensity stimulation of hippocampal circuits can produce NMDA-mediated epileptiform discharges in the dentate gyrus.

Action Potentials↗
PubMed1988

Hippocampal slices from kindled rats show an increased sensitivity for induction of epileptiform activity by changes in extracellular ion concentrations.

The ability of increases in extracellular potassium ([K+]o) and/or decreases in extracellular calcium ([Ca2+]o) to induce epileptiform activity in hippocampal slices was studied by systematically varying [K+]o and [Ca2+]o. Slices prepared from kindled rats, both 1 week and 1 month after the last kindled seizure, showed an increased sensitivity to perturbations of both ions. Stimulus-locked epileptiform discharges occurred with small displacements of [K+]o and/or [Ca2+]o. The ionic threshold for spontaneous epileptiform discharges was not significantly affected. This long-lasting change in sensitivity to the ionic environment produced by the kindling process had important implications for epileptogenesis in chronically epileptic tissue.

Action Potentials↗
PubMed1988

Phenytoin does not block hippocampal long-term potentiation or frequency potentiation.

Recently, a theoretical scheme offered mechanisms by which phenytoin exerts its antiepileptic effects. Two predictions arising from this proposal are that phenytoin would suppress alterations in the potency of excitatory neurotransmission engendered by repetitive neural activation and that this effect would be augmented by displacing the extracellular concentration of K+ ([K+]0) away from its normal resting level. In the present study, we tested these predictions by examining the effects of phenytoin on short- and long-term functional plasticity in vitro in the hippocampus. Extracellular field potentials were recorded in the CA1 region of the rat hippocampal slice in response to stimulation of the Schaeffer collaterals. Phenytoin (20 micrograms/ml) did not affect baseline excitatory neurotransmission as measured by input-output curves (population spike amplitude versus stimulus intensity) obtained at low stimulus rates. The drug also had no effect on either frequency potentiation (2.5 Hz) or long-term potentiation (50 Hz, 500 msec; or 400 Hz, 20 msec). When [K+]0 was raised to levels seen during seizures, the drug still did not alter frequency potentiation or long-term potentiation induced by either type of stimulus train. Phenytoin also had no effect on either stimulus-locked or spontaneous epileptiform bursts that appear in conjunction with elevated [K+]0 or on stimulus-locked bursts that appear in the presence of 0.75 mM extracellular calcium. These results, showing that certain forms of functional synaptic plasticity are not affected by phenytoin, suggest a means by which phenytoin could exert its antiepileptic action without interfering with normal brain function.

Animals↗
PubMed1988

In vitro effects of extracellular calcium concentrations on hippocampal pyramidal cell responses.

This study examined the effects of varying the extracellular Ca2+ concentration [( Ca2+]o) on membrane stabilization, response to paired stimuli, and long-term potentiation (LTP) in the CA1 pyramidal cells of the rat hippocampal slice. To approximate the in vivo state, 1.5 mM [Ca2+]o was used as the control condition. Raising [Ca2+]o caused a leftward shift of the input-output curve (stimulus intensity vs population spike amplitude) and reduced the tendency toward multiple spiking. Lowering [Ca2+]o shifted the input-output curve down and to the right. When [Ca2+]o was lowered to 0.75 mM an epileptiform pattern of extracellular field responses was produced. Paired-pulse phenomena were studied at an interstimulus interval of 20 ms using both input-output curves and action potential thresholds for single units. Only facilitation was seen using single unit thresholds. Using input-output curves, inhibition was seen in 2.5 and 3.5 mM [Ca2+]o at high stimulus intensities but not at all in 1.5 mM [Ca2+]. LTP was shown to be Ca2+-dependent, maximal at 1.5 mM [Ca2+]o and absent at 1.0 mM [Ca2+]o. LTP was present but less prominent in [Ca2+]o greater than 1.5 mM.

Animals↗
PubMed1988

Epileptiform discharges induced by altering extracellular potassium and calcium in the rat hippocampal slice.

During and after intense neuronal activity the concentration of extracellular potassium ([K+]o) increases while the concentration of calcium ([Ca2+]o) decreases. The present study examined the effect of increased [K+]o alone, and with a parallel decrease in [Ca2+]o, on overall excitability, long-term potentiation (LTP), and the appearance of epileptiform discharges. [K+]o and [Ca2+]o were varied over the range in which they fluctuate in vivo. Hippocampal slices were first equilibrated in a control artificial CSF containing 3.1 mM K+ and 1.5 mM Ca2+ and then reequilibrated in an identical solution except that the K+ was increased to 3.55, 4, 5, 6, or 8 mM with and without a decrease in Ca2+ to 1.0 mM. Raising [K+]o caused a leftward shift of input-output curves. Lowering [Ca2+]o to 1.0 mM had no effect on the ability of [K+]o to shift the input-output curve to the left. LTP was not changed by increasing [K+]o. Lowering [Ca2+]o to 1.0 mM blocked LTP and increasing the [K+]o did not overcome this blockade. When [K+]o alone was altered, the [K+]oS at which epileptiform bursts occurred 50% of the time were 5.6 and 7.6 mM for stimulus-locked and spontaneous bursting, respectively. The combination of decreased [Ca2+]o and increased [K+]o made slices considerably more prone to epileptiform activity. In 1.0 mM [Ca2+]o, the [K+]o at which 50% of the slices showed stimulus-locked bursting was decreased to 3.6 mM while that for spontaneous discharges was 5.4 mM. The sensitivity of hippocampal slices to [K+]o and [Ca2+]o, and the synergistic actions of alterations of these ions, indicates that even small changes in the aggregate extracellular ionic milieu may be important in epileptogenesis.

Animals↗
PubMed1986

Local synaptic interactions in the rat striatum in vitro: a quantitative analysis based on unit discharges.

The functioning of local circuits in the striatum maintained in vitro was studied using a new quantitative means to analyze single-unit responses. Measurements of the threshold for monosynaptically activated neurons to each of the stimuli in a paired-pulse protocol were made at various interstimulus intervals. The difference in thresholds between the first (conditioning) and second (test) stimuli was found to be independent of absolute threshold intensity, but to vary linearly with the interstimulus interval. From this information threshold difference versus interstimulus interval curves were constructed and shown to be constant from neuron to neuron under a given experimental condition, but to change in different ionic and drug environments. Such curves demonstrated: a change from paired-pulse facilitation in a [Ca2+] of 1.5 mM to paired-pulse inhibition in a [Ca2+] of 3.5 mM; a lack of effect of reserpine treatment on paired-pulse responses; and an enhancement of paired-pulse facilitation with physostigmine. The agreement of these results with the findings provided by other types of analysis validates the approach outlined here which offers a number of advantages for studying intrinsic striatal synapses.

Acetylcholine↗
PubMed1983

Blockade of long-term potentiation by phencyclidine and sigma opiates in the hippocampus in vivo and in vitro.

Long-term potentiation (LTP) of synaptic transmission in the rat hippocampus in vivo and in vitro, was studied using field potentials. Pretreatment with phencyclidine (PCP) or 'sigma' opiates blocked LTP in vivo while mu and kappa opiates and the antagonist naloxone were ineffective. Scopolamine (20 mg/kg i.p.) neither prevented LTP nor antagonized the LTP-blocking effect of PCP. In vitro, PCP up to 100 microM did not alter synaptic activation of CA1 pyramidal cells by stratum radiatum stimulation but blocked LTP in a dose-dependent manner (ED50: 3 microM). The sigma opiate, cyclazocine, also prevented the induction of LTP in vitro while morphine and procaine were ineffective.

Animals↗
PubMed1982

Effect of phencyclidines on hippocampal pyramidal cells.

Phencyclidine (PCP) and several behaviorally active or inactive structural analogs were administered i.v. to urethane-anesthetized rats in order to determine their effects on CA1 pyramidal cell discharges elicited by contralateral CA3 (cCA3) stimulation. PCP and the behaviorally active m-amino derivative (m-NH2 PCP) depressed, in a dose-dependent manner, the amplitude of the population spike evoked in CA1 by a cCA3 stimulation (ED 50s: 0.9 mg/kg for PCP, 0.5 mg/kg for m-NH2 PCP). However, the behaviorally inactive derivatives m-nitro (m-NO2 PCP) and PCP methyliodide (PCP CH3I) were ineffective up to 10 mg/kg. PCP (0.1-0.3 mg/kg i.v.) also decreased the duration of inhibition of CA1 discharges in a paired-stimulus paradigm; this was in contrast to the effects of thiopental and diazepam. In midcollicular-transected, urethane-anesthetized rats, the inhibitory effect of PCP on cCA3-CA1 transmission was not observed but the drug was still as effective as in intact rats in the paired-stimulus paradigm. In animals subjected to 6-hydroxydopamine lesions of the hippocampal noradrenergic innervation (average 85%) decrease in NE content), the potency of PCP in inhibiting cCA3-CA1 transmission was the same as in a group of sham-operated controls. These results suggest the following conclusions: (i) PCP exerts at least 2 separate types of effects in CA1, both of which result from a central action of the drug; (ii) PCP decreases the monosynaptic excitation of CA1 pyramidal cells and this action requires the integrity of brainstem afferents; (iii) PCP may decrease recurrent inhibition or afterhyperpolarization in CA1 via a mechanism which is independent of these connections and, therefore, could result from a direct action of the drug at the level of the hippocampus; (iv) finally, no evidence was found to suggest that the noradrenergic innervation of the hippocampus is critically involved in the action of PCP on CA1 discharges.

Animals↗
PubMedDate not supplied

Model of spontaneous hippocampal epilepsy in the anesthetized rat: electrographic, [K+]0, and [Ca2+]0 response patterns.

These experiments present a model of spontaneous epileptiform activity that can be produced acutely in the urethane-anesthetized rat. Extracellular potential changes were recorded in CA1 or the dentate gyrus along with measurements of extracellular potassium ([K+]0) and calcium ([Ca2+]0) throughout 90 min of continuous stimulation to the contralateral CA3 region and for up to 4 h afterwards. During the continuous stimulation, both brain regions showed a cyclic pattern of electrographic seizures. Immediately upon stopping the stimulation, spontaneous epileptiform activity continued for up to 90 min in both CA1 and dentate gyrus. A quiescent period without electrographic activity was followed by the return of spontaneous epileptiform activity an average of 2 h after the end of stimulation. The excitability of the system was depressed after the continuous stimulation and gradually recovered during the quiescent period before the onset of the spontaneous epileptiform activity. [K+]0 increased during, not before, each seizure (both during the continuous stimulation and during the delayed spontaneous epileptiform activity) and remained elevated as long as neuronal discharges occurred. [Ca2+]0 transiently decreased with the onset of electrographic activity and never decreased before the appearance of epileptiform discharges.

Action Potentials↗
PubMedDate not supplied

Interaction of phenobarbital and phenytoin in an experimental model of seizures in rats.

The combination of phenobarbital (PB) and phenytoin (PHT) was recommended for many years for treatment of epilepsy in humans. We tested the effectiveness of the combination in a model of hippocampal seizures termed maximal dentate activation (MDA). Two parameters of MDA were measured: duration and time to onset. Neither the vehicle controls nor PHT 80 mg/kg had an effect on duration or time to onset of MDA. PB 20 mg/kg delayed the normal increase in MDA duration and had no effect on time to onset. Addition of increasing doses of PHT to the 20-mg/kg dose of PB caused a dose-dependent decrease in MDA duration and a dose-dependent increase in time to onset. These effects do not appear to be due to an increase in serum level of either drug when administered together. We showed that the combination of PB and PHT has actions in an experimental model of limbic seizures that are not produced by either drug alone. Therefore, clinical use of the combination does have some experimental justification.

Animals↗