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E W Lothman

Publications and source records attributed to E W Lothman.

At least 91 records · Page 5Linked to original sources
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↗
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↗
PubMed1987

Somatostatin augments the spread of limbic seizures from the hippocampus.

The role of the neuropeptide somatostatin in limbic seizures was studied using electrical stimulation of the hippocampus in kindled rats. Cysteamine, an agent which selectively and reversibly depletes brain somatostatin stores, had a biphasic action. An early proconvulsant effect was seen within a few hours, consisting of prolonged electrographic seizures in the hippocampus and more severe behavioral convulsions. A later anticonvulsant effect, maximal at 1 to 2 days and dissipating within a week, was manifested by less intense behavioral convulsions without change in the duration of electrical seizure activity. Both effects were dose-dependent. No change in afterdischarge thresholds was detected at any time after the administration of cysteamine. Intraventricular administration of somatostatin to animals with behavioral seizures attenuated by cysteamine treatment restored the responses to precysteamine levels. We conclude that somatostatin facilitates the spread of seizures over limbic circuits from a region of focal seizure initiation.

Animals↗
PubMed1987

In vitro and in vivo distribution and binding of phenytoin to rat brain.

The distribution and binding of phenytoin (PHT) were studied in rat brain using anatomically intact tissue. The pattern and kinetics of PHT distribution in vivo were examined with quantitative carbon-14 autoradiography. Initially gray matter levels were greater than white matter levels, but after 30 min the opposite condition was found. At a given time point, the levels of PHT among various gray matter structures as a group or among white matter structures as a group were uniform. The ratio of radioactivity in white matter to that in gray matter was 3:1 120 min after injection of radiolabeled PHT. Thin-layer chromatography showed only PHT in the brain 15 min after injection of PHT and both PHT and its hydroxylated metabolite [5-(p-hydroxyphenyl)-5-phenylhydantoin] 120 min after injection. The proportions of PHT and 5-(p-hydroxyphenyl)-5-phenylhydantoin were the same in white as in gray matter. Direct chemical measurements of brain samples obtained after coinjections of tracer amounts of radiolabeled PHT with increasing doses of unlabeled PHT corroborated the autoradiographic findings and revealed no displacement of the tracer by pharmacologic doses of the unlabeled drug. In vitro binding of PHT was investigated with sections obtained from frozen brains and with physiologically intact brain slices. Both high (4-10 nM) and low (1 microM) affinity conditions were examined. In no case was specific binding detected. Binding was greater in gray matter than in white matter in sections, whereas binding was greater in white matter than in gray matter in slices. We conclude that PHT distribution and binding reflect physico-chemical factors, such as lipid content, and physiological factors, such as blood flow and selective partitioning into white matter in living tissue, rather than specific receptors.

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↗
PubMed1986

Functional metabolic mapping during forelimb movement in rat. I. Stimulation of motor cortex.

The quantitative 14C-deoxyglucose (DG) autoradiographic technique has been used to study changes in cerebral metabolism during forelimb movements induced by graded stimulation of motor cortex. Experiments were directed at studying basic physiologic and anatomic aspects of the metabolic changes. Single shocks caused movement without metabolic change, whereas low-frequency trains caused seizures. Repetitive high-frequency train stimuli of short duration (500 Hz for 20 msec) caused jerk movements coupled with DG uptake in pathways. With stimulation of the forelimb motor zone at frequencies of 15-30/min there was prominent activation of cortical columns and strips in ipsilateral SI, SII, and MII, and contralateral MI and SI. Higher frequencies (120/min) were required to cause significant changes in DG in subcortical circuits. The most prominent changes occurred within a longitudinal corridor in dorsal thalamus and a ventral corridor in second-order sites in basal ganglia. Metabolic activation also occurred in contralateral cerebellum, the cuneate nucleus, and dorsal horn of the cervical spinal cord. Changes in these latter two sites were largely eliminated by removing feedback sensory activity. Stimulation of the forelimb sensory zone activated different sites in caudatoputamen and thalamus but similar zones in midbrain and cerebellum. The magnitude of the metabolic response in distant sites depended on the frequency of cortical stimulation. Different frequency-response relationships in different sites seemed to reflect the nature of the cortical input as well as differential effects of anesthesia. The pattern of the metabolic response was studied by comparing sites of activation with sites of the anatomic projections from motor and sensory cortical zones. 3H- and 14C-labeled amino acids were used to map the site and relative strength of pathways. Results revealed good correlation between the site of anatomic projection and the site of DG uptake but no consistent relationship between the relative strength of a projection and the magnitude of metabolic change within its field. Changes in glucose utilization with metabolic mapping experiments depend on the nature, strength, and frequency of stimulation; the site and nature of anatomic projection; the effects of anesthesia; and the strength of sensory feedback associated with the induced behavior.

Animals↗
PubMed1985

Kindling with rapidly recurring hippocampal seizures.

Bipolar electrodes, stereotactically implanted in the hippocampus of adult rats, were used to deliver 10 s trains of suprathreshold tetanic electrical stimuli every few minutes. As indices of seizure intensity, durations of the afterdischarges triggered by these stimuli were measured, and the accompanying behaviors were scored on a 5-point scale. After 2-3 h, prolonged afterdischarges appeared in conjunction with severe limbic seizures, separated by periods of approximately 60 min. After 3-9 h, the stimulation was withheld until the following day. Upon reinstitution of the stimuli, intense seizures were seen at the onset, and the cycle time between them was shortened. Enhanced responsiveness to a fixed stimulus persisted for several months, the longest period tested. In addition, the enhanced epileptogenicity showed transference and was not stimulus-specific. These studies, using stimuli with low intertrain frequency and short interstimulus intervals, establish a robust and rapidly-developing model of epileptogenesis in the hippocampus that is comparable to traditional kindling.

Animals↗
PubMed1985

Functional mapping of limbic seizures originating in the hippocampus: a combined 2-deoxyglucose and electrophysiologic study.

The pathways by which seizures spread from the hippocampus were studied both with multiple electroencephalographic recordings and 2-deoxyglucose autoradiography. The rapid kindling model described in the previous report was employed to compare mild versus severe limbic seizures. Seizures were accompanied by an increased glucose utilization in localized brain areas. The transition from mild to severe limbic seizures involved a greater spatial extent of paroxysmal electroencephalographic activity and metabolic signals. However, electrical recordings proved more sensitive in mapping seizures, as regions shown to be involved in mild or severe limbic seizures with electrical recordings did not necessarily show an increased glucose metabolism. Three types of circuits are important in dissemination of these seizures: interhippocampal connections, pathways leading out of the hippocampus to other limbic regions, and connections to certain extralimbic areas. The nucleus accumbens, amygdala, and substantia nigra emerge as important relay points in the spread of hippocampal-based seizures.

Animals↗
PubMed1983

Functional anatomy of limbic seizures: focal discharges from medial entorhinal cortex in rat.

Focal seizure discharges were induced in the ventral aspect of the medial entorhinal cortex of awake, freely moving rats, either with cannula injections of penicillin or picrotoxin (0.02 microliters every 10-15 min) or by repetitive tetanic electrical stimulation. [14C]Deoxyglucose autoradiography (DG) was performed when animals were in a 'steady-state' with respect to electrographic discharges and/or behavioral changes. During simple interictal spikes behavior remained normal and DG labeling was increased only in the entorhinal focus and stratum moleculare of the ventral dentate gyrus. With complex spikes and short seizures animals exhibited staring, decreased responsiveness, and occasional wet dog shakes. DG labeling was increased in all layers of the dentate gyrus, Ammon's horn (ipsilateral greater than contralateral) and, to a lesser degree, in ipsilateral amygdala, and the accumbens-ventral pallidum area. During strong seizures, rearing and forelimb clonus occurred and metabolism was strongly activated bilaterally in the hippocampal formation, amygdala, accumbens, substantia nigra, and the anterior and periventricular thalamic nuclei. These studies indicate that the dentate gyrus initially restricts the entry of seizures from entorhinal cortex into the rest of hippocampus. As this is overcome there is rapid bilateral spread through the hippocampal formation with passive interruption of normal behavior. With prolonged seizure discharges there is further capture of amygdala and subcortical extrapyramidal and thalamic nuclei associated with behavioral convulsions.

Animals↗
PubMed1983

Cellular and synaptic basis of kainic acid-induced hippocampal epileptiform activity.

The effects of kainic acid (KA) were studied using extracellular and intracellular recordings in the hippocampal slice preparation. In sufficient concentrations, KA led to a loss of all evoked responses. However, the amount of drug needed for this varied according to anatomic region. CA3 was more sensitive (1 microM) than CA1 or the dentate gyrus (10 microM). These results can be understood in terms of a profound and long-lasting depolarization of neurons. Lower concentrations of KA (0.05-0.1 microM) did not change the resting membrane potential or input resistance of hippocampal pyramidal cells but produced spontaneous epileptiform activity which originated in CA3 and propagated to CA1. Epileptiform discharges were not present in the dentate gyrus. Coincident with the induction of paroxysms, the following changes were observed: (1) an increase in the excitability of CA3 and CA1 pyramidal cells as measured by a left shift in the input-output curves of evoked responses and a lowered threshold stimulus intensity necessary for activation of action potentials in single neurons; (2) augmentation and synchronization of bursting in pyramidal cells; and (3) prolonged EPSPs without an increase in their amplitude. These findings indicate that multiple changes, involving both the properties of single neurons and synaptic connections, are involved in the development of hippocampal paroxysms and that CA3 and CA1 have different roles in the generation of these discharges.

Animals↗
PubMed1983

Blood-brain barrier changes with kainic acid-induced limbic seizures.

Rats were treated with kainic acid (KA) i.v. to produce increasingly severe limbic seizures that were monitored with a behavioral rating scale. At various times after the induction of seizures, the animals; blood-brain barriers (B-BB) were studied with alpha-[14C]aminoisobutyric acid ([14C]AIBA) autoradiography. Using optical density ratios, a coefficient was devised to assess the functional integrity of the B-BB in discrete anatomic regions and to quantitatively compare these measurements among different groups of experimental animals. In animals that exhibited only mild seizures, the B-BB was not different from controls. Animals with severe limbic seizures, however, showed alterations. For as long as 2 h after delivery of KA, the B-BB appeared normal; from 2 to 24 h, the permeability to [14C]AIBA was markedly increased throughout the brain, especially in limbic regions; from 24 h to 7 days the B-BB returned to normal except for a small residual change in limbic structures. These findings were confirmed with Evans blue dye studies of the B-BB. A correlation between focal accentuation of B-BB alterations and neuropathologic changes was found. These experiments indicted that recurrent limbic seizures may lead to a breakdown in the B-BB independent of systemic metabolic derangements. Marked focal metabolic and electrical changes, however, occurred in several limbic structures several hours before the blood-brain barrier was altered.

Aminoisobutyric Acids↗
PubMed1983

Learning deficits after lesions of dentate gyrus granule cells.

The effect of destroying granule cells in the dentate gyrus on learning was examined with a behavioral testing protocol. These neurons were destroyed by microinjections of the selective neurotoxin colchicine in the hippocampal formation of rats. After a 30-day recovery period, the animals were trained in an operant chamber with an appetitive conditioning paradigm. The learning abilities of the animals with lesions were compared with two control groups--naive, unoperated rats and those with control injections of saline. The basic task required the animal to discriminate between two spatially separate visual stimuli which represented positive and negative cues. Testing and training was separated into four progressively more difficult phases with various stimulus schedules, contingencies of reinforcement, and stimulus positions. Colchicine-treated animals demonstrated significantly poorer performance than naive animals and those receiving saline control injections. None of the colchicine-treated animals achieved criterion performance in the stimulus position reversal paradigm, and half had difficulty with variable ratio schedules of reinforcement. Our experiments suggested that granule cells in the dentate gyrus played a pivotal role in certain learning tasks.

Animals↗