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J L Stringer

Publications and source records attributed to J L Stringer.

At least 55 records · Page 3Linked to original sources
PubMed1992

Amygdala stimulation produces two types of hippocampal afterdischarges in the urethane-anesthetized rat.

How seizures spread during epileptiform events has been the subject of intensive investigation over the years. The present study explored the relationship between the amygdala and the hippocampus during afterdischarges. Stimulating electrodes were placed in the amygdala and CA3 regions on the left side in urethane-anesthetized rats. Recording microelectrodes were placed in the dentate gyrus on the left and the CA1 cell layer on the right. Afterdischarges were elicited by stimulus trains between 10 and 50 Hz to the amygdala. Most of the afterdischarges consisted of broad positive potentials in dentate gyrus and no shift of the DC potential. When the stimulus trains were repeated, the afterdischarge evolved, first by spreading to the contralateral side and then by the appearance of maximal dentate activation. The onset of maximal dentate activation was indicated by the appearance of bursts of large amplitude population spikes and a negative shift of the DC potential. These data demonstrate that two types of afterdischarges can be produced in the hippocampus of the anesthetized rat after amygdala stimulation. The observations support the hypothesis that maximal dentate activation represents synchronized reverberatory activity throughout the hippocampal-parahippocampal circuit and indicate that amygdala stimulation can access this circuit in the anesthetized animal.

Action Potentials↗
PubMed1992

Reverberatory seizure discharges in hippocampal-parahippocampal circuits.

Previously, a unique type of epileptiform discharge, recorded in the dentate gyrus, has been identified and termed maximal dentate activation. Maximal dentate activation is defined by the presence of bursts of large amplitude population spikes, associated with a secondary rise in the extracellular potassium and a negative shift of the dc potential. Prior work has linked maximal dentate activation to lengthening of afterdischarges when they are elicited in the hippocampus or outside of the hippocampus in the amygdala. The current study used two approaches to further examine the relationship of maximal dentate activation to seizures in limbic circuits in urethane-anesthetized rats. First, simultaneous recordings were employed to document that during maximal dentate activation, synchronous discharges occurred in the dentate gyrus, cornu Ammonis, subiculum, and entorhinal cortex. From anatomical work, these structures are known to be connected in a hippocampal-parahippocampal loop. The second approach used lesions of the entorhinal cortex to document the importance of this loop in the initiation and maintenance of maximal dentate activation. Both electrolytic and chemical (focal injections of tetrodotoxin) lesions of the entorhinal cortex blocked maximal dentate activation on the side of the lesion. However, maximal dentate activation was maintained on the opposite side, where the hippocampal-parahippocampal loop was intact. Altogether, these data support the hypothesis that maximal dentate activation is a marker for the presence of reverberatory, synchronized paroxysmal activity throughout the hippocampal-parahippocampal loop and that this loop behaves as a unit in epileptogenesis.

Animals↗
PubMed1992

Bilateral maximal dentate activation is critical for the appearance of an afterdischarge in the dentate gyrus.

Recently, a phenomenon has been described in the dentate gyrus termed maximal dentate activation, which is defined by the appearance of bursts of large amplitude population spikes associated with a negative shift of the d.c. potential and a secondary rise of the extracellular potassium level. Previous work has linked maximal dentate activation to kindling of afterdischarges, either when they are elicited in the hippocampus or outside of the hippocampus in the amygdala. Recording bilaterally in the dentate gyrus, it was found that maximal dentate activation occurred on both sides, with the side ipsilateral to the stimulus (either CA3 or angular bundle) being activated first. An afterdischarge did not appear unless bilateral maximal dentate activation had occurred. With repeated stimulation, the time to onset of maximal dentate activation on the two sides of the brain became nearly equal. This was associated with the appearance of afterdischarges. However, complete synchronization of the onset of maximal dentate activation was not necessary for afterdischarge production. Maximal dentate activation and afterdischarges could be readily elicited in rats in which the hippocampal commissures had been cut. It appears that, in the intact brain, the lack of maximal dentate activation on one side of the brain can function as a "brake" for epileptic activity, preventing afterdischarges. Once this brake is removed, by cutting the hippocampal commissures or by initiating maximal dentate activation, the dentate gyrus readily expresses afterdischarges.

Amygdala↗
PubMed1992

The dentate gyrus as a control point for seizures in the hippocampus and beyond.

Considerable in vitro work has pointed to a resistance of dentate gyrus granule cells for expressing epileptiform paroxysms. However, in vivo work has shown that these neurons, under appropriate conditions, support and sustain seizure discharges. This range of activity of granule cells, along with their location in the middle of a pathway that connects hippocampal regions with high propensities for generating seizures, allows the dentate gyrus to act as a critical regulator of seizures. In the following report we review experiments on a stereotyped, robust paroxysmal discharge, maximal dentate activation (MDA), that occurs in granule cells, and we examine the role of MDA in reinforcing seizures in hippocampal circuits. In addition, work is presented that indicates MDA regulates seizures at sites beyond the hippocampus and its connections. Other studies that examine morphological and functional changes in the local circuits of granule cells and other neurons in the dentate gyrus in different models of epilepsy are discussed. We conclude that the dentate gyrus functions in several modes during seizures, even in the naive brain, and that in chronic epilepsy alterations take place that provide an even greater diversity of functional capabilities. Explicating these heterogeneous conditions will provide important insight into basic mechanisms of seizures and epileptogenesis.

Afferent Pathways↗
PubMed1991

Maximal dentate activation is produced by amygdala stimulation in unanesthetized rats.

In urethane-anesthetized rats, a process termed maximal dentate activation has been shown to be associated with the lengthening of afterdischarges that occurs with repeated hippocampal stimulation. Maximal dentate activation is a unique paroxysmal form of epileptiform discharges consisting of large amplitude population spikes in the dentate gyrus. The current experiments examined the relationship of maximal dentate activation to kindling of motor seizures in the awake animal. Both long duration (5 or 10 s) and short duration (1 s) stimulus trains in either the hippocampus or the amygdala were effective in eliciting maximal dentate activation. Repeated stimulation of the amygdala produced lengthening of afterdischarges and kindling of motor responses, but only after maximal dentate activation had appeared in response to the stimulus. Over the course of amygdala kindling, the duration of maximal dentate activation lengthened with increasing severity of behavioral seizures. This evidence supports the hypothesis that maximal dentate activation is a marker for the presence of seizures distributed throughout limbic circuits. In addition, the data suggest that maximal dentate activation may be an important process involved in the acquisition of kindled responses.

Amygdala↗
PubMed1991

Cholinergic and adrenergic agents modify the initiation and termination of epileptic discharges in the dentate gyrus.

A unique type of limbic seizures, maximal dentate activation, was used to examine the effects of cholinergic and adrenergic agents on the processes involved in epileptogenesis. The time to onset of maximal dentate activation was used to monitor the initiation of seizures while the duration of maximal dentate activation monitored termination of seizures. The cholinergic agonist pilocarpine shortened maximal dentate activation at 20 mg/kg and lengthened maximal dentate activation at 50 mg/kg, while both doses delayed the onset of maximal dentate activation. Atropine, a cholinergic antagonist, at 50 mg/kg, slowed the rate of lengthening of maximal dentate activation that occurred with repeated stimulation. The beta-adrenergic antagonist propranolol also slowed the rate of lengthening of maximal dentate activation at 3 mg/kg and shortened maximal dentate activation at 10 mg/kg. The alpha 2-agonist clonidine, at 0.5 mg/kg, shortened maximal dentate activation and increased the time to onset; at 0.1 mg/kg, clonidine did not affect maximal dentate activation. Pretreatment with reserpine had no effect on either the time to onset or duration of maximal dentate activation. These results indicate that both cholinergic and adrenergic mechanisms play important roles in the initiation and termination of limbic seizures.

Animals↗
PubMed1990

A1 adenosinergic modulation alters the duration of maximal dentate activation.

The role of adenosine systems in the initiation and termination of seizures was examined using a unique marker for limbic seizures--maximal dentate activation (MDA). At 10 mg/kg 2-chloroadenosine shortened the duration of MDA, a measure of seizure terminating processes. The selective A1 agonist, cyclopentyladenosine, at 3 mg/kg, blocked the increase in duration of MDA, while the A1 antagonist, 1,3-dipropyl-8-cyclopentylxanthine (0.05 mg/kg) had the opposite effect. None of the compounds tested altered the time to onset of MDA, a measure of processes that initiate seizures. Therefore, modulation of A1 adenosine systems appears to alter seizure termination much more than seizure initiation.

2-Chloroadenosine↗
PubMed1990

Pharmacological evidence indicating a role of GABAergic systems in termination of limbic seizures.

The role of inhibitory systems in the initiation and termination of seizures in limbic circuits of the rat was tested by measuring the time to onset and duration of maximal dentate activation before and after the administration of GABAergic agents. Both 0.1 and 0.3 mg/kg of the GABAA receptor antagonist bicuculline lengthened maximal dentate activation while 0.3 mg/kg was needed to reversibly decrease the time to onset. Picrotoxin, an antagonist at the GABAA receptor/channel complex, lengthened maximal dentate activation, but did not alter the time to onset. Muscimol, a GABAA receptor agonist, shortened maximal dentate activation, but did not lengthen the time to onset. Baclofen, a GABAB receptor agonist (3 and 10 mg/kg), had no effect on the time to onset of maximal dentate activation, while 10 mg/kg baclofen shortened maximal dentate activation. These results demonstrate that agents that have selective action at both GABAA and GABAB synapses alter the duration of maximal dentate activation more than they influence the time to onset of maximal dentate activation and suggest that GABAergic mechanisms are critical in the termination of seizures.

Animals↗
PubMed1990

Maximal dentate activation: a tool to screen compounds for activity against limbic seizures.

A model of partial complex (limbic) seizures in the anesthetized rat based on the phenomenon of maximal dentate activation was used to study the effect of various known antiepileptic drugs. Maximal dentate activation consists of a distinct triad of large amplitude population spikes, associated with a rise in [K+]0 to 10 mM and a negative shift of the DC potential. Repeated stimulation produces lengthening of the duration of maximal dentate activation (mimicking the lengthening of afterdischarges that occurs during kindling) and a decrease in the time to onset of maximal dentate activation. Diazepam (3 mg/kg), carbamazepine (50 mg/kg) and phenobarbital (60 mg/kg) caused a reversible reduction in the duration of maximal dentate activation. Carbamazepine (30 mg/kg) and phenobarbital (20 mg/kg) prevented the lengthening of maximal dentate activation that occurs with repeated elicitation while phenytoin (80 mg/kg), ethosuximide (300 mg/kg) and valproic acid (300 mg/kg) had no effect. The doses of these known antiepileptic drugs agree with the doses efficacious against limbic seizures in awake rats. This suggests that the ability to shorten the duration of maximal dentate activation provides a useful means to screen compounds for activity against partial complex seizures.

Animals↗
PubMed1990

Use of maximal dentate activation to study the effect of drugs on kindling and kindled responses.

Maximal dentate activation is a paroxysmal event characterized by the appearance of bursts of large amplitude population spikes in the dentate gyrus that has been shown to be associated with the production of afterdischarges in limbic circuits. Repeated elicitation of maximal dentate activation in the anesthetized rat produces a progressive increase in afterdischarge duration. The present work examined the role of NMDA receptor activation in this process. The effects of MK-801 (a systemically active NMDA receptor complex antagonist) and imipramine and desipramine (tricyclic antidepressants recently reported to have NMDA receptor-coupled channel blocking properties) were studied. MK-801, at 0.5 mg/kg, prevented the lengthening of the duration of maximal dentate activation. At 2 mg/kg, MK-801 also shortened the duration of maximal dentate activation already established. Imipramine showed a similar dose-dependent response pattern with 15 mg/kg and 50 mg/kg respectively. Desipramine (50 mg/kg) was similar to imipramine (50 mg/kg) in its effect. Thus, the drugs studied were effective at shortening limbic epileptiform discharges. These results support the use of this model to examine drug effects and strengthen the hypothesis that NMDA receptors play a critical role in seizure generation in the limbic system and, specifically, in the lengthening of the duration of maximal dentate activation.

Animals↗
PubMed1990

Recurrent spontaneous hippocampal seizures in the rat as a chronic sequela to limbic status epilepticus.

A period of continuous hippocampal stimulation (CHS) establishes an acute condition of self-sustaining limbic status epilepticus (SSLSE) which is followed by chronic neuropathological changes reminiscent of hippocampal sclerosis encountered in epileptic patients. In the chronic (greater than or equal to 1 month) condition following CHS-induced SSLSE, extended electrographic monitoring in the hippocampus revealed spontaneous recurrent paroxysmal discharges. All 6 animals studied had persistent interictal spiking; 3 had multiple fully developed electrographic seizures. There was a marked diminution of paired pulse inhibition, demonstrated by a protocol known to reflect the potency of inhibition mediated by GABAA receptors. Hippocampal slices from animals that had previously experienced CHS-induced SSLSE demonstrated an increased excitability relative to slices from control animals as evidenced by epileptiform bursting in increased extracellular potassium ([K+]0) and decreased extracellular calcium ([Ca2+]0). These studies establish that CHS-induced SSLSE in rats provides an experimental model with recurrent spontaneous hippocampal seizures. Based on electrophysiological data we suggest that a decrease in GABA-mediated inhibition and/or altered sensitivity to extracellular ions may play roles in the development of such seizures.

Action Potentials↗
PubMed1989

Repetitive seizures cause an increase in paired-pulse inhibition in the dentate gyrus.

A paired-pulse stimulus protocol was used to measure angular bundle to dentate gyrus paired-pulse inhibition in rats before and after the occurrence of 36 or 72 seizures elicited from the contralateral CA3 region. The seizures showed progressive lengthening. There was a moderate increase in paired-pulse depression 1 h after 36 seizures and a further increase after 72 seizures. These data demonstrate that the same experimental protocol which produced a decrease in paired-pulse inhibition in the CA1 region caused the opposite effect in the dentate gyrus.

Anesthesia↗
PubMed1989

In vitro and in vivo transplantation of fetal rat brain cells following incubation with various anatomic tracing substances.

Implantation of fetal brain regional anlage into host brains ('brain transplantation') holds promise as a plausible treatment for certain human neurodegenerative disorders. Improvements in experimental brain transplantation techniques include: (1) utilization of brain cells in tissue culture as opposed to freshly prepared cell suspensions as a transplantation source, (2) prelabeling of fetal brain cells with inert, non-toxic tracer substances to allow subsequent (a) unequivocal identification of those cells as being fetally derived, and (b) anatomical and immunohistochemical identification of transplanted neurons, and (3) development of in vitro models for transplantation to allow physiological studies of connections formed between fetal neurons and host brain tissue. We examined the ability of brain cell suspensions derived from rat fetuses 15-17 gestational days old to accumulate and retain anatomic tracing substances, including Phaseolus vulgaris leucoagglutinin (PHA-L), rhodamine-labeled latex microspheres (RLM) and fluorogold (FG). All tracers were rapidly accumulated by fetal brain cells, but only PHA-L and RLM were retained following implantation into adult hosts or in tissue culture in vitro. PHA-L-labeled fetal brain cells transplanted in vivo showed morphological characteristics similar to fetal neurons kept in tissue culture in vitro. RLM- or PHA-L-labeled fetal brain cells can be co-cultured with rat brain slices maintained in long-term roller culture. This in vitro system will allow identification and physiological or immunohistochemical study of interactions between fetally derived and host brain neurons.

Animals↗
PubMed1989

Effect of volatile anesthetics on synaptic transmission in the rat hippocampus.

The synaptic effects of halothane, isoflurane, and enflurane were examined in the rat hippocampus in vivo and compared with the effects of ketamine and urethane. Actions of the agents on excitatory amino acid-mediated neurotransmission were studied by observing evoked responses and long-term potentiation in the stratum pyramidale of CA1 with stimulation of the contralateral CA3 region. Long-term potentiation is a long-lasting increase in synaptic efficacy, which follows a brief stimulus train. It has been shown to be established through activation of the NMDA subclass of excitatory amino acid receptors and is thought to be involved in memory processing. Volatile anesthetics had no effect on evoked excitatory responses or on long-term potentiation. Actions of the anesthetics on inhibitory processes in the hippocampus were studied by pairing stimuli at a range of interpulse intervals. The first stimulus activated inhibitory processes that caused the response to the second stimulus to be smaller than the initial response, a phenomenon termed paired pulse depression. Paired pulse depression was significantly prolonged by the volatile anesthetics compared with that under urethane or ketamine. These results indicate that the mechanism of action of the volatile anesthetics at the hippocampal CA1 synapse does not involve amino acid-mediated excitation but does involve enhancement of inhibition.

Animals↗
PubMed1989

Evidence that repetitive seizures in the hippocampus cause a lasting reduction of GABAergic inhibition.

1. A method was developed to quantify paired-pulse depression of population spikes in the CA1 region of the hippocampus of urethane-anesthetized rats with paired stimuli to the contralateral CA3 region at various states of excitability of pyramidal cells. This method was applied to measure changes following recurrent seizures, a single seizure, or long-term potentiation (LTP). 2. In naive animals paired-pulse depression was highly variable at low stimulus intensities, but constant above a certain "threshold" stimulus intensity. The potency of paired-pulse depression also depended on the time between paired stimuli, being maximal at an interpulse interval of 20 ms. The general relationships of paired-pulse depression to stimulus intensity and to interpulse interval were unaltered after LTP, after a single seizure, and after recurrent seizures, but there were quantitative changes in the last two cases. 3. A variety of pharmacologic agents known to interact with GABAergic inhibition were studied for their effect on paired-pulse depression. These agents affected earlier phases of paired-pulse depression (interpulse intervals less than or equal to 100 ms). The GABA agonist muscimol and the benzodiazepine diazepam enhanced paired-pulse depression whereas the GABA antagonist bicuculline decreased it. 4. Repeated seizures elicited by trains (50-Hz, 10-s durations every 5 min) of electrical stimuli to the hippocampus were associated with progressive lengthening of afterdischarges. 5. Recurrent seizures caused a statistically significant reduction in the potency of earlier phases of paired-pulse depression. There was an increase in the potency of later phases of paired-pulse depression after recurrent seizures, but this was not statistically significant. These changes were present for at least 2 h after the last seizure. 6. An antidromic-orthdromic paired-pulse protocol was used to exclude slow conductance changes as the cause of paired-pulse depression. Paired-pulse depression measured with this method was also decreased by recurrent seizures. 7. A single seizure caused a small reduction in paired-pulse depression that dissipated in less than an hour. 8. A single seizure caused LTP of stimulus intensity versus population spike curves whereas recurrent seizures attenuated or even reversed the potentiation, leading to a rightward shift of the curves relative to control curves. When LTP was produced by a less intense stimulus train (50-Hz, 400-ms duration), there were no associated seizures nor was there any change in paired-pulse depression.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Induction of paroxysmal discharges in the dentate gyrus: frequency dependence and relationship to afterdischarge production.

1. Electrical-stimulus trains activated hippocampal circuits in urethan-anesthetized rats. Responses were monitored with recordings of extracellular potentials and with measurements of the extracellular potassium ([K+]o). Stimulating electrodes were placed in the CA3 region contralateral to the recording electrode (cCA3) and in the ipsilateral angular bundle (AB) while recording in the CA1 pyramidal-cell layer or the granule-cell layer of the dentate gyrus. Patterns of maximal activation were identified. 2. In the CA1 region, maximal activation was indicated by the presence of 10- to 15-mV population spikes, a smooth rise in [K+]o of 5-6 mM above base-line levels of 3 mM, and a negative shift of the sustained DC potential of 2-4 mV. The dentate gyrus was considered to be maximally activated when bursts of large-amplitude (20-40 mV) population spikes were present. These population spikes were associated with a secondary rise in [K+]o to 6-8 mM above base line and an abrupt negative shift of the DC potential of 5-8 mV. 3. Maximal activation depended on the stimulus intensity, frequency, and duration. Trains of 10-Hz stimuli were used to determine the lowest stimulus intensity needed to elicit complete activation in CA1 and in the dentate gyrus. At this intensity, afterdischarges were not produced, and these responses could be elicited repeatedly. 4. By the use of this threshold stimulus intensity, cCA3 stimulation produced a rapid and progressive augmentation of CA1 responses until maximal activation was reached. In comparison, stimulation of the AB could produce the same end result, but the appearance of CA1 population spikes was delayed. Stimulation of the AB produced a steady increase in the evoked granule-cell population spike until the appearance of the paroxysmal large-amplitude population spikes. In contrast, cCA3 stimulation produced two positive evoked responses in the dentate gyrus before the paroxysms of population spikes began. 5. The frequency dependence of the responses was determined by giving stimulus trains ranging from 2 to 100 Hz. Stimulation of cCA3 produced population spikes in CA1 up to 100 Hz that were all associated with the same peak rise in [K+]o. AB stimulation only produced CA1 responses with stimulation frequencies between 15 and 25 Hz. The paroxysmal dentate population spikes were generated by stimulus frequencies between 15 and 30 Hz with both AB and cCA3 stimulation. 6. Unilateral colchicine injections caused a loss of dentate granule cells and a loss of maximal dentate activation on the side of the injection.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Maximal dentate gyrus activation: characteristics and alterations after repeated seizures.

1. The dentate gyrus was activated by trains of stimulation to either the contralateral CA3 region or the ipsilateral angular bundle. Responses were monitored with recordings of extracellular field potentials and extracellular potassium ([K+]o. Maximal dentate activation was identified by the appearance of bursts of large-amplitude (20-40 mV) population spikes associated with a secondary rise in [K+]o and an abrupt negative shift of the DC potential. 2. Several parameters were defined to characterize features of maximal dentate activation. These included 1) time to onset of maximal dentate activation, 2) duration of maximal dentate activation, 3) stimulus threshold for maximal dentate activation, 4) threshold for afterdischarge production, and 5) afterdischarge durations. The time to onset of maximal dentate activation and the duration of maximal dentate activation depended on the stimulus intensity until, above a certain stimulus intensity, both parameters reached constant values. The total period of maximal dentate activation (during both stimulation and afterdischarge) was constant. 3. The characteristics of maximal dentate activation were then determined in kindled animals and compared with age-matched controls. Kindled animals had a significant increase in the total duration of maximal dentate activation and a decrease in the ratio of afterdischarge threshold to the threshold for maximal dentate activation to 1 from a ratio in control animals of 6. 4. In a set of urethan-anesthetized animals, the characteristics of maximal dentate activation before and after 36 stimuli were determined. One hour after the last of 36 stimulus-evoked seizures, there was a trend towards a decrease in the threshold for maximal dentate activation and in the time to its onset.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗