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Biomedical subjects

W A Wilson

Publications and source records attributed to W A Wilson.

At least 19 recordsLinked to original sources
PubMed1992

Suppression of interictal bursting in hippocampus unleashes seizures in entorhinal cortex: a proepileptic effect of lowering [K+]o and raising [Ca2+]o.

The relation between interictal bursts (IIBs) and seizures in epilepsy is obscure. Results from some human and animal studies suggest that IIBs may actually suppress seizure activity. This appears particularly true in the zero magnesium in vitro seizure model. Here we provide new evidence in support of this and new insight into the mechanisms of seizure suppression in this model. Brain slices containing hippocampus and entorhinal cortex were bathed in zero magnesium medium. Electrographic seizures appeared, then were replaced by IIBs. Upon lowering [K+]o and raising [Ca2+]o the IIBs disappeared and the seizures reappeared. Repeated stimuli mimicking IIBs then suppressed seizures again. Selective knife cuts revealed that the IIBs originated in the hippocampus (area CA3) whereas the seizures originated in entorhinal cortex. These results confirm that IIBs suppress seizures in the zero magnesium model. They also show that an important aspect of the interaction between IIBs and seizures in this model is the anatomical segregation of their respective sites of origin. This may apply in other models and in human epilepsy as well. Finally, these results illustrate that one consequence of the anatomical segregation and mutual interaction of IIBs and seizures is that influences which are locally pro- or antiepileptic can have opposite effects in a broader region.

Action Potentials↗
PubMed1992

The GABAB receptor antagonist, CGP-35348, inhibits paired-pulse disinhibition in the rat dentate gyrus in vivo.

Extracellular field potentials were recorded from the dentate gyrus of adult rats during electrical stimulation of the angular bundle in vivo. Paired pulses produced inhibition of the second population spike (PS2) at 25 ms, and potentiation at inter-stimulus intervals from 50 to 200 ms. The GABAB receptor antagonist, CGP 35348, reduced the amplitude of PS2 at each of these inter-stimulus intervals while producing no effect on the first population spike of the pair (PS1). Under control conditions, the duration of the second population EPSP (pEPSP2) was increased relative to the first at inter-stimulus intervals from 100 to 400 ms, and CGP 35348 reduced these durations to baseline levels. These results demonstrate that GABAB receptors modulate synaptic inhibition in vivo.

Animals↗
PubMed1992

The role of GABAB receptor activation in absence seizures of lethargic (lh/lh) mice.

Lethargic (lh/lh) mice, which function as an animal model of absence seizures, have spontaneous seizures that have behavioral and electrographic features and anticonvulsant sensitivity similar to those of human absence seizures. Antagonists of the gamma-aminobutyric acidB (GABAB) receptor suppressed these seizures in lethargic mice, whereas agonists of GABAB receptors exacerbated them. Furthermore, GABAB receptor binding and synaptically evoked GABAB receptor-mediated inhibition of N-methyl-D-aspartate responses were selectively increased in lh/lh mice. Therefore, enhanced GABAB receptor-mediated synaptic responses may underlie absence seizures in lh/lh mice, and GABAB receptor antagonists hold promise as anticonvulsants for absence seizures.

Animals↗
PubMed1991

Ethanol inhibition of NMDA mediated depolarizations is increased in the presence of Mg2+.

The inhibitory potency of ethanol upon excitatory amino acid induced depolarizations of rat hippocampal CA1 pyramidal cells was assessed in the presence and absence of magnesium (Mg2+) using the grease-gap technique. Ethanol shifted the N-methyl-D-aspartate (NMDA) dose-response curves to the right in a non-parallel manner. In the presence of Mg2+, ethanol appeared to be a more effective NMDA antagonist (IC50 47 mM) than in the absence of Mg2+ (IC50 107 mM). The IC50 for ethanol upon non-NMDA mediated CA1 pyramidal cell depolarizations was in excess of 170 mM. These results strongly suggest a preferential inhibitory action of ethanol against NMDA, rather than non-NMDA, mediated responses. Experiments in which ethanol and Mg2+ were covaried indicated that these substances act by two distinct mechanisms to antagonize the action of NMDA. These effects of ethanol, at concentrations which elicit intoxication (less than 50 mM) but not anesthesia, suggest that the NMDA receptor complex may play an important role in the acute effects of ethanol.

Animals↗
PubMed1991

Ethanol and magnesium ions inhibit N-methyl-D-aspartate-mediated synaptic potentials in an interactive manner.

The role of magnesium ions in the inhibitory effect of ethanol on NMDA receptor-mediated population synaptic potentials (pEPSPs) in area CA1 of the hippocampus of the adult rat, was studied. The excitatory amino acid (non-NMDA) receptor antagonist, DNQX and the GABAA channel antagonist, picrotoxin, were used to pharmacologically isolate NMDA-mediated pEPSPs. In the presence of a physiological concentration of magnesium (1.0 mM), ethanol (25-100 mM) inhibited NMDA-mediated pEPSPs, with an apparent EC50 of approximately 50 mM. The ability of ethanol to inhibit NMDA-mediated pEPSPs was reduced when the slices were incubated in the absence of magnesium. Concentrations of ethanol, in the range of 50-200 mM (apparent EC50 100 mM), were required to inhibit NMDA-mediated pEPSPs, in the absence of added magnesium. Combination studies of these two antagonists indicated that the sensitivity of NMDA-mediated pEPSPs to one antagonist was not altered by the presence of the other. This finding suggests that the affinity of each antagonist binding site is not affected by the presence of the other antagonist. In the case of ethanol, its low maximum antagonist efficacy may require larger concentrations of ethanol to inhibit NMDA-mediated pEPSPs, in the absence of other non-competitive antagonists such as magnesium.

Animals↗
PubMed1991

GABAB-receptor-mediated inhibition of the N-methyl-D-aspartate component of synaptic transmission in the rat hippocampus.

GABA receptor regulation of NMDA-receptor-mediated synaptic responses was studied in area CA1 of the rat hippocampus using extracellular and intracellular recording techniques. Picrotoxin (PTX) was used to suppress GABAA inhibition and 6,7-dinitroquinoxaline-2,3-dione (DNQX) was used to suppress non-NMDA receptor-mediated responses. In this manner, we were able to avoid the complicating factors caused by potentials induced by other excitatory and inhibitory amino acid receptors. Under these conditions, large NMDA-receptor-mediated EPSPs were observed. When paired stimuli were given at interstimulus intervals from 100 to 400 msec, powerful inhibition of the second response was observed. This inhibition was reversed by the GABAB antagonists phaclofen and 2-hydroxy-saclofen; it was also depressed by removal of Mg2+ from the bath. Examination of non-NMDA receptor-mediated synaptic responses (determined in the presence of D-2-amino-5-phosphonovalerate and PTX) showed no such inhibition, thereby supporting the hypothesis that GABAB inhibition of NMDA EPSPs is postsynaptic. This difference in paired-pulse inhibition of NMDA and non-NMDA EPSPs leads us to conclude that there was no evidence of GABAB-mediated presynaptic inhibition of excitatory transmitter release. Intracellular recordings in the presence of DNQX and PTX revealed a phaclofen-sensitive late IPSP that correlated in time with the period of inhibition of NMDA responses. Taken together, these data suggest that paired-pulse-inhibition of NMDA responses is produced by a GABAB-receptor-mediated hyperpolarization of the postsynaptic membrane, causing an enhanced block of the NMDA channels by Mg2+. Regulation of NMDA-mediated synaptic responses by GABAB receptors constitutes a powerful mechanism for control of a major excitatory system in hippocampal pyramidal cells.

Animals↗
PubMed1991

Anticardiolipin antibodies in unselected pregnant women. Relationship to fetal outcome.

Anticardiolipin antibodies (ACLA) have recently been associated with adverse fetal outcome. The prevalence of elevated ACLA has not been studied in unselected pregnant women, however. Twelve hundred unselected pregnant women were screened for IgG ACLA using an assay standardized by the first international workshop on ACLA. Fifteen (1.25%) were positive for IgG ACLA (greater than 3 SD above the mean) but only 0.5% had moderate to high levels of IgG ACLA (greater than 5 SD above the mean). Low levels of IgG ACLA were not associated with increased risk of fetal loss; however, 50% of women with moderate to high levels of antibody had fetal wastage. These findings further support the association of significantly elevated levels of IgG ACLA with fetal loss.

Adolescent↗
PubMed1990

Cross-modal performance: behavioural processes, phylogenetic considerations and neural mechanisms.

Issues relating to cross-modal performance (CMP) are examined from various points of view, with major emphasis on phylogenetic comparisons and neurological mechanisms. Although it now seems likely that certain distinctions that were made based on training procedures (i.e., among transfer, matching, and recognition) have no functional significance, research on this topic has demonstrated how the level of performance is affected by certain task variables (such as number of trials in the first modality). It has not yet been shown that these relationships differ from ones that would be seen in comparable within-modal studies. Overall phylogenetic differences specific to CMP cannot be sustained from the data for humans, apes, monkeys, and non-primates. However, two possible differences--one phylogenetic and one ontogenetic--require further study. Metaphorical matching has not been demonstrated in nonhumans, and it may be the case that 'categorical' CMP appears earlier in development than 'specific' CMP. Efforts to establish that CMP is mediated by representations localized in regions of polysensory neural convergence have not provided convincing evidence, so that 'leakage' between perceptual/memory systems previously considered to be modality-specific is proposed as the mechanism for CMP. Based primarily upon findings from a study using 2-DG, the suggestion is made that one pathway for such leakage is through the ventral claustrum. Polysensory areas of cortex may play a special role during the initial formation of a multisensory engram.

Animals↗
PubMed1990

Regenerative, all-or-none electrographic seizures in the rat hippocampal slice in Mg-free and physiological medium.

All-or-none electrographic seizures (EGSs) were studied in hippocampal slices from young (21- to 38-day-old) rats in medium containing low (0 mM) or physiological (0.9 mM) levels of magnesium, with and without the GABAB agonist baclofen. Extracellular recording and stimulation were performed in stratum pyramidale and stratum radiatum of CA3, respectively. EGS activity was induced by exposure to low-Mg medium or by delivering repetitive stimulus trains in physiological Mg medium. After EGS activity had stabilized, the EGSs were tested for all-or-none behavior by varying the number of pulses in a train. An EGS was considered all-or-none if subthreshold stimulation produced no afterdischarge bursts, and if the EGS duration was largely independent of the number of suprathreshold stimulus pulses. According to this measure, EGSs in Mg-free + baclofen medium were all-or-none. EGSs evoked in physiological Mg medium were also all-or-none, although the threshold was higher, and the EGS duration lower, than in Mg-free medium. This all-or-none characteristic was observed whether the EGSs were induced by prior exposure to Mg-free medium or by repetitive stimulation, and in the presence and absence of baclofen. The all-or-none characteristic suggests that while the triggering mechanism for EGSs is strongly dependent on stimulus intensity, regenerative mechanisms--independent of stimulus intensity--are responsible for the maintenance of EGSs. EGSs are also terminated by mechanisms not dependent on stimulus intensity.

Action Potentials↗
PubMed1990

Reduced sensitivity of the N-methyl-D-aspartate component of synaptic transmission to magnesium in hippocampal slices from immature rats.

This study describes the measurement of N-methyl-D-aspartate (NMDA)-mediated excitatory postsynaptic potentials (EPSPs) of the CA1 subregion of transverse hippocampal slices from immature and adult rats. Our methods permit extracellular measurement of NMDA-mediated depolarizations in the presence of magnesium (Mg2+) ions. In comparison to slices from adult rats (75-90 days old), NMDA EPSPs in hippocampus from immature rats (25-35 days old) were of significantly greater amplitude and were significantly less sensitive to magnesium. It is suggested that developmental plasticity may be related to changes in magnesium regulation of the NMDA channel complex.

Aging↗
PubMed1990

Baclofen facilitates the development of long-term potentiation in the rat dentate gyrus.

The effect of baclofen on the development of long-term potentiation (LTP) in the dentate gyrus was examined. Stimulus trains applied to the perforant path in the presence of baclofen produced significantly more potentiation of the perforant path-evoked response than did similar stimulation in control medium. In addition, baclofen enabled stimulus trains, ordinarily subthreshold for LTP induction, to produce LTP. These results demonstrate that GABAB receptor activation by baclofen makes repetitive stimulation more effective at producing LTP.

Action Potentials↗
PubMed1990

Increased ectopic action potential generation accompanies epileptogenesis in vitro.

We studied changes in the characteristics of action potentials of CA3 pyramidal cells accompanying electrographic seizure (EGS) induction, using an in vitro model similar to kindling. We found an increased propensity to fire action potentials which lack EPSPs or other triggering depolarizing potentials. Such 'baseline spikes' appear to be initiated at a site electrically distant from the soma.

Action Potentials↗
PubMed1990

MK-801 potently inhibits alcohol withdrawal seizures in rats.

The ability of MK-801, an N-methyl-D-aspartate (NMDA)-channel antagonist, to suppress alcohol withdrawal seizures generated audio-genically was studied in adult male rats using a cross-over experimental design. MK-801 treatment reduced overall seizure score and proportion of rats seizing. In comparison to other seizure models, alcohol withdrawal seizures seem to be particularly sensitive to MK-801, suggesting that mechanisms which result in seizure susceptibility after withdrawal of chronic ethanol exposure may be dependent upon sensitization or upregulation of NMDA processes.

Acoustic Stimulation↗
PubMed1990

MK-801 impedes the acquisition of a spatial memory task in rats.

Several studies have reported that MK-801 impairs the acquisition of various learning and memory tasks, while others suggest that MK-801 may interfere with performance rather than having a specific effect on memory. To characterize further the effects of MK-801 on learning and memory, MK-801 (0.05 mg/kg, SC) was administered prior to or immediately after learning trials in a trial-independent water maze task. Since MK-801 may affect nonassociative variables that may influence learning and memory, motor activity and general reactivity measures were also determined for 0.0125, 0.025, or 0.05 mg/kg of MK-801 administered SC. Since MK-801 may also be used to treat children with epilepsy, we investigated the possible persistent cognitive effects on neonates. MK-801 (0.02 mg/kg, SC) was administered at postnatal days 9-15 and tested in the same task as above starting at day 36 of age. There were no persistent effects of neonatal treatment. However, in adult rats, MK-801 impaired the acquisition of the water maze task but did not affect performance during a recall task in the same apparatus. At doses affecting learning, there were no effects on motor activity or general reactivity in adult rats. These results are consistent with the conclusion that MK-801 interferes with acquisition of spatial learning in the rat.

Aging↗
PubMed1990

Opioid-induced epileptiform bursting in hippocampal slices: higher susceptibility in ventral than dorsal hippocampus.

The disparity between the seizure sensitivity of the dorsal and ventral hippocampus to opioid peptides was studied by an in vitro electrophysiological method. Slices taken from the ventral (temporal) and dorsal (septal) regions of rat hippocampi were perfused in artificial cerebrospinal fluid bubbled continuously with 95% O2-5% CO2 at 34 degrees C. A stimulating electrode was placed in the stratum radiatum of CA3 region and electrical activity was recorded from the pyramidal cell body layer of the CA3b region. Paired dorsal and ventral hippocampal slices were perfused with [N-Me-Phe3-D-Pro4]morphiceptin (PL017), a specific mu opioid receptor agonist. Application of 0.05 microM PL017 produced triggered and spontaneous bursting in 20% of ventral hippocampal slices, but no such effect was observed in dorsal hippocampal slices. At 0.5 microM PL017, 80% of ventral hippocampal slices developed spontaneous bursting, whereas only 10% of dorsal hippocampal slices had spontaneous bursting. Slices from the ventral hippocampus consistently produced greater degrees of bursting at lower doses relative to the dorsal hippocampus. The addition of 0.1 microM naloxone before or after PL017 inhibited the triggered response but could not block the spontaneous bursting. Perfusion of ACSF for 1 hr also eliminated the triggered response but could only reduce the frequency of the spontaneous bursting. These results suggest that the ventral hippocampus has a higher susceptibility to PL017-induced epileptiform bursting, and this effect is mediated, at least in part, through mu opioid receptors.

Animals↗