Biomedical subjects

W C Abraham

Publications and source records attributed to W C Abraham.

At least 55 records · Page 3Linked to original sources

PubMed1994

Cysteamine potentiates entorhinal activation of dentate gyrus granule cells in rats.

A dense plexus of somatostatin-positive fibers and varicosities is observed in the outer two-thirds of the dentate gyrus molecular layer where the glutamatergic perforant path afferents from the entorhinal cortex terminate. To test for a functional interaction between these two pathways, we examined the effects of cysteamine, which enhances somatostatin release for a few hours after administration but produces subsequent depletion of somatostatin lasting several days, on perforant path evoked potentials recorded in the dentate gyrus. Cysteamine (50-400 mg/kg, IP) increased the population spike dose-dependently both in anesthetized and in awake rats, but the slope of the population excitatory postsynaptic potential (EPSP) was left unchanged or even decreased. The antidromic population spike evoked by mossy fiber stimulation was not changed by cysteamine. The change is thought to be due to the increase in slope of the EPSP-spike relationship. In the hippocampal slice preparation, a similar effect of the drug (1-5 mM) on dentate evoked potentials was observed, suggesting that cysteamine acts through its effects on somatostatin in the hippocampus itself. In chronically implanted awake animals, the perforant path population spike was increased 1 h after cysteamine but returned to the predrug level by 24 h when somatostatin seemed to be depleted. These results suggest that hippocampal somatostatin released by cysteamine potentiates the response of dentate granule cells to perforant path input, without directly affecting synaptic transmission or general cell excitability.

Anesthesia↗

PubMed1993

Comparison of associative and non-associative conditioning procedures in the induction of LTD in CA1 of the hippocampus.

Recent reports have indicated that weak activity in a test input, negatively correlated (out-of-phase) with tetanization of a separate, converging input, produces an NMDA-independent, associative long-term depression (LTD) of the test input synapses, in hippocampal field CA1 (Stanton and Sejnowski, 1989; Stanton et al., 1991). Associative LTD has also been observed in the dentate gyrus, in vivo, but only following "priming" of the test path with 5 Hz stimulation prior to associative conditioning (Christie and Abraham, 1992b). We have used these stimulus protocols, in vitro, in order to compare the induction of non-associative and associative LTD in field CA1 of the adult rat hippocampus. Stimulation in normal solution evoked a small non-associative LTD, but no associative LTD. Addition of picrotoxin to the medium facilitated the induction of NMDA-dependent non-associative LTD, but not associative LTD. Previously potentiated pathways were not different from naive pathways in expression of LTD of either kind. Finally, 'priming' stimulation (5 Hz) of the test pathway produced a weak, selective enhancement of associative LTD that was, however, not significantly greater than non-associative LTD. These results indicate that, for our experimental conditions, negatively correlated co-activity during afferent tetanization does not induce a substantial associative LTD in area CA1.

2-Amino-5-phosphonovalerate↗

PubMed1993

Differential expression of immediate early genes after hippocampal long-term potentiation in awake rats.

The pattern of expression of fos and jun family immediate early genes following the induction of long-term potentiation (LTP) was investigated in the dentate gyrus of awake rats. Rapid, transient increases in the levels of c-jun and jun-B mRNA and protein, and in the levels of Fos-related proteins (FRAs), occurred in the dentate gyrus after LTP-inducing tetanization of the perforant path. A delayed, and more prolonged induction occurred for jun-D mRNA and protein. The induction of c-Jun, Jun-B, Jun-D and Fos-related proteins was prevented by administration of an N-methyl-D-aspartate receptor antagonist, which also blocked LTP induction, and by pentobarbital, which reduced but did not block LTP. These findings show that differential expression of fos and jun gene family members occurs in a distinct pattern following LTP in awake rats. The responsive genes may participate in the biochemical cascade leading to the long-term stabilization of synaptic modifications.

Animals↗

PubMed1993

Correlations between immediate early gene induction and the persistence of long-term potentiation.

The duration of long-term potentiation in the dentate gyrus of awake rats was examined following systematic manipulation of the number of stimulus trains delivered. This was correlated with the induction of immediate early genes in separate groups of animals given identical stimulus regimes. Following 10 trains of stimulation, long-term potentiation decayed with a time constant of up to several days (long-term potentiation 2), and this correlated with the appearance of an increase in the messenger RNA and protein levels of zif/268. Increasing the number of stimulus trains resulted in a greater probability of eliciting long-term potentiation with a time constant of several weeks (long-term potentiation 3), as well as increasing the induction of zif/268, c-Jun, Jun-B, Jun-D and Fos-related proteins. When 10 trains were delivered repeatedly on up to five consecutive days, only the zif/268 protein levels showed associated changes. These data provide support for the hypothesis that long-term potentiation 3 involves mechanisms additional to those for long-term potentiation 2. One possible mechanism is altered gene expression, initiated by immediate early gene transcription factors such as zif/268 and possibly homo- or heterodimers of Fos and Jun family members, that then contributes to the stabilization or maintenance of long-term potentiation 3.

Animals↗

PubMed1992

Correlation between the induction of an immediate early gene, zif/268, and long-term potentiation in the dentate gyrus.

Expression of the immediate early gene zif/268 (also termed NGFI-A, Krox 24, TIS8 and Egr-1) was investigated in awake rats following various long-term potentiation (LTP) induction protocols. zif/268 mRNA (Northern blots) and protein (immunohistochemistry) levels sharply increased following LTP, and followed a time course characteristic of other immediate early genes. When measured across 3 tetanization protocols known to produce differing degrees of LTP persistence, zif/268 induction was found to be more highly correlated with LTP duration than with the magnitude of initial LTP. These data support the hypothesis that the immediate early gene zif/268 plays a role as a third messenger in the cascade of cellular and nuclear events that govern the persistence of LTP.

Animals↗

PubMed1992

NMDA-dependent heterosynaptic long-term depression in the dentate gyrus of anaesthetized rats.

This report examines the inductive mechanisms involved in long-term heterosynaptic depression (LTD) in the dentate gyrus of anaesthetized rats. Associative and non-associative stimulus protocols were implemented, using the ipsilateral medial and lateral perforant path inputs to the dentate gyrus as the test pathways. In all experiments, the medial perforant path (MPP) received the conditioning stimuli which consisted of eight stimulus trains of 2 s duration, spaced 1 minute apart. Within each train the stimuli occurred as a burst of 5 pulses at 100 Hz, repeated at 200 ms intervals. The lateral perforant path (LPP) served as the test pathway in all of the initial experiments. In the associative condition, it received single pulses equally spaced between the medial path bursts. In the non-associative condition, no lateral path stimuli were given during the medial path trains. In both conditions, the application of the conditioning stimuli resulted in a long-term potentiation (LTP) of the medial path evoked responses (P less than 0.001), while the lateral path responses showed LTD (P less than 0.001). A two-way analyses of variance revealed there to be no difference between the two paradigms in the expression of LTP or LTD in naive pathways or in their ability to depress a potentiated pathway (P greater than 0.05) An occlusion test also showed there to be no further decreases in synaptic efficacy with the associative paradigm after the lateral path synapses were saturated with non-associative LTD.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1992

Priming of associative long-term depression in the dentate gyrus by theta frequency synaptic activity.

Associative long-term synaptic depression (LTD) was investigated utilizing negatively correlated activity patterns in the medial and lateral perforant path inputs to the dentate gyrus in anesthetized rats. Normally only nonassociative, or heterosynaptic, LTD is elicited in naive pathways. We report here, however, that associative LTD in the lateral path is readily induced after being "primed" by a brief period of lateral path synaptic activity at a theta rhythm frequency (5 Hz). Priming of associative LTD lasts at least 2 hr and is not seen following priming activity at non-theta frequencies (1 and 15 Hz). N-methyl-D-aspartate receptor activation is critical for establishing the priming effect, but not for the subsequent induction of the associative LTD. These data suggest that theta rhythm activity in the dentate gyrus may predispose the system to a specific form of synaptic plasticity, associative LTD.

Animals↗

PubMed1991

The involvement of L-type calcium channels in heterosynaptic long-term depression in the hippocampus.

The involvement of L-type calcium channels in heterosynaptic long-term depression (LTD) of the stratum radiatum input to area CA1 was studied in rat hippocampal slices. LTD of the radiatum field excitatory postsynaptic potential (EPSP) and population spike, produced by tetanization of the alveus in the presence of picrotoxin, was blocked by the calcium antagonist nimodipine and by a monoclonal antibody to the L-type calcium channel. LTD was produced in the absence of picrotoxin when the L-type calcium channel agonist, BAY-K8644, was applied. This effect was also blocked by nimodipine. These results indicate that L-type calcium channels are involved in heterosynaptic long-term depression.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1991

Heterosynaptic long-term depression is facilitated by blockade of inhibition in area CA1 of the hippocampus.

Non-associative long-term depression (LTD) of the stratum radiatum input to area CA1 was studied in rat hippocampal slices. Tetanization of either the alveus or stratum oriens produced greater than 30 min depression of the radiatum field EPSP and population spike, but generally only in the presence of picrotoxin. The spike depression was accounted for by the EPSP depression, and could be blocked by prior administration of an N-methyl-D-aspartate receptor antagonist. These data suggest that the induction of non-associative LTD is depolarization-dependent and involves the N-methyl-D-aspartate receptor/channel complex.

Animals↗

PubMed1991

The role of immediate early genes in the stabilization of long-term potentiation.

Immediate early genes (IEGs) are a class of genes that show rapid and transient but protein synthesis-independent increases in expression to extracellular signals such as growth factors and neurotransmitters. Many IEGs code for transcription factors that have been suggested to govern the growth and differentiation of many cell types by regulating the expression of other genes. IEGs are expressed in adult neurons both constitutively and in response to afferent activity, and it has been suggested that during learning, IEGs may play a role in the signal cascade, resulting in the expression of genes critical for the consolidation of long-term memory. Long-term potentiation (LTP) is a persistent, activity-dependent form of synaptic plasticity that stands as a good candidate for the mechanism of associative memory. A number of IEGs coding for transcription factors have been shown to transiently increase transcription in the dentate gyrus of rats following LTP-inducing afferent stimulation. These include zif/268 (also termed NGFI-A, Krox-24, TIS-8, and egr-l), c-fos-related genes, c-jun, junB, and junD. Of these, zif/268 appears to be the most specifically related to LTP since it is evoked under virtually all LTP-inducing situations and shows a remarkably high correlation with the duration of LTP. There are a number of outstanding questions regarding the role of zif/268 and other IEGs in LTP, including which second messenger systems are important for activating them, which "late effector" genes are regulated by them, and the exact role these genes play, if any, in the stabilization and maintenance of LTP.

Animals↗

PubMed1990

Chlordiazepoxide reduces discriminability but not rate of forgetting in delayed conditional discrimination.

Benzodiazepine and anticholinergic drugs interfere with septo-hippocampal function in similar but not identical ways. They also share a number of common behavioural effects and, in particular, both classes of drug interfere with spatial memory in the Morris Water Maze--a test which is very sensitive to hippocampal dysfunction. We have previously shown that the anticholinergic drug scopolamine impairs discriminability, but not rate of forgetting, in delayed conditional discrimination. In the present study forgetting was quantified by fitting a negative exponential function to estimates of discriminability derived from a signal detection analysis of data from an auditory delayed conditional discrimination task. Chlordiazepoxide produced a highly significant decrease in discriminability which was monotonically related to the logarithm of dose in the range 0.67-18.0 mg/kg IP. The rate of forgetting was not increased. These data confirm the pharmacological independence of changes in discriminability and rate of forgetting; demonstrate that in this task chlordiazepoxide has similar effects to scopolamine; and suggest that the effects of chlordiazepoxide in other working memory tasks could be more a result of changed stimulus processing than impairment of memorial processes.

Animals↗

PubMed1990

Effects of the NMDA antagonists CPP and MK-801 on radial arm maze performance in rats.

The dose- and time-dependent effects of N-methyl-D-aspartate receptor/channel antagonists on radial 8-arm maze performance were examined in rats. Both CPP (1.0-30 mg/kg), a competitive NMDA antagonist, and MK-801 (0.1-1.0 mg/kg), a noncompetitive NMDA antagonist, produced dose-dependent increases in the number of errors made to sample all 8 baited arms. The effective doses of both drugs produced maximal performance impairments 2 hr after IP injection, and no effects after 24 hr. In a second radial arm maze task where only 4 arms were baited, CPP (10 mg/kg) had a somewhat greater effect on the number of working memory errors than on reference memory errors. MK-801 (0.1, 0.33 mg/kg) had no effects on either this task or on a task involving a 1-hr delay between correct choices 4 and 5 on the 8 choice task. CPP (10 mg/kg), however, impaired performance on this latter task. These results indicate that doses of NMDA antagonists, sufficient to block hippocampal long-term potentiation, also disrupt radial arm maze performance.

Animals↗

PubMed1990

Induction of Fos-like immunoreactivity and the maintenance of long-term potentiation in the dentate gyrus of unanesthetized rats.

Memory formation in the mammalian central nervous system may require long-lasting alterations in gene expression. However, it is not yet known whether the candidate memory mechanism long-term potentiation (LTP) requires alterations in gene expression for its maintenance, nor the extent to which the time course of LTP can be manipulated at the time of induction. In this study we influenced the time course of LTP decay for the perforant path input to the dentate gyrus in awake rats by manipulating conditions at the time of induction, and correlated the outcome with the induction of c-fos protein(s) (Fos), as measured immunohistochemically in the dentate gyrus of separate animals 2 h post-tetanization. Sodium pentobarbital, which blocks the induction of Fos-like immunoreactivity (Fos-IR), also blocked a long-duration form of LTP maintained over weeks. On the other hand, two different patterns of delivery of 50 trains, that produced similar time courses of LTP decay, produced markedly different degrees of Fos-IR induction. In addition, while stimulation consisting of only 10 trains induced a sizable Fos response, it only produced LTP lasting a few days. When the 10-train stimulation was repeated on 3 or 5 consecutive days, there appeared to be no additional Fos-IR induction, yet the LTP decay time constant was considerably prolonged. Thus there is little correlation between the degree of Fos-IR induction and the subsequent durability of LTP.

Animals↗

PubMed1990

Time-dependent pro- and anticonvulsant effects of cysteamine on the development and expression of amygdaloid kindled seizures.

The time-dependent pro- and anticonvulsant effects of cysteamine, a depletor of somatostatin, were investigated on the development and expression of amygdaloid kindled seizures. Acute administration of cysteamine (25-400 mg/kg, i.p.) produced a dose-dependent potentiation of kindled seizures when evoked 4 h after the drug. However, the seizures initiated 1 day after drug administration were dose-dependently suppressed. Furthermore, elicitation of seizures 4 h after cysteamine enhanced its anticonvulsant effects at 1 day after the drug, causing a parallel left shift of the dose-response curve. Since it has been reported that somatostatin is released during generalized seizures, the seizures given 4 h after cysteamine may encourage the somatostatin depletion by cysteamine and thereby potentiate its later anticonvulsant effects. The repeated administration of cysteamine (100 mg/kg, i.p.) during kindling development strongly retarded the development of generalized seizures but not the development of focal seizures or of afterdischarges in the amygdala. In contrast to the acute experiments, kindling stimulation given 4 h after each cysteamine treatment did not augment the blocking effect on kindling development. These data indicate that chronic cysteamine treatment has a strong inhibitory effect on the development of amygdaloid kindling.

Amygdala↗

PubMed1989

Inhibition of protein synthesis in the dentate gyrus, but not the entorhinal cortex, blocks maintenance of long-term potentiation in rats.

We examined whether the critical protein synthesis for maintenance of perforant path long-term potentiation (LTP) takes place in the dentate gyrus or the entorhinal cortex. Field potential recordings were made of responses in the dentate gyrus to stimulation of the perforant path in urethane-anaesthetized rats. Anisomycin (10 micrograms) injected into the dentate gyrus, but not the entorhinal cortex, 1 h prior to tetanization led to nearly complete decay of perforant path LTP of the excitatory postsynaptic potential (EPSP) within 3 h. Intra-dentate injection of neither actinomycin D (a mRNA synthesis inhibitor) nor boiled anisomycin affected LTP maintenance over 6 h. These results suggest that the proteins necessary for the maintenance of LTP over 6 h are synthesized in the dentate gyrus from already existing mRNA without involving protein synthesis in the cell bodies of the afferent fibres.

Action Potentials↗

PubMed1989

Long-term potentiation and the induction of c-fos mRNA and proteins in the dentate gyrus of unanesthetized rats.

We tested the hypothesis that the nuclear proto-oncogene c-fos is involved in long-term potentiation (LTP) of the perforant path-dentate gyrus synapse in awake freely moving rats. High-frequency stimulation that produced LTP induced c-fos mRNA and protein in the dentate granule cells but not in CA1, CA3, or the entorhinal cortex. However, the degree of LTP induction did not correlate with the degree of c-fos induction. Agents that interfered with the production of LTP (e.g. NMDA antagonists) also prevented c-fos induction. Low-frequency stimulation did not lead to either LTP or c-fos induction. However, c-fos induction did not necessarily follow LTP production because some high-frequency stimulation protocols that produced good LTP did not lead to c-fos induction. Thus, c-fos induction is clearly not related to LTP production in unanaesthetized rats, but it remains to be determined if it plays some role in LTP maintenance.

Adaptation, Physiological↗

PubMed1989

Effects of the NMDA antagonists CPP and MK-801 on delayed conditional discrimination.

N-methyl-D-aspartate (NMDA) receptor/channel antagonists have previously been shown to impair spatial working memory and hippocampal long-term potentiation. The present experiment investigated the effects of a variety of doses of NMDA antagonists on a working memory task in rats involving an auditory delayed conditional discrimination. Signal detection analysis and an exponential memory decay model were used to extract independent measures of stimulus discriminability and rate of forgetting. A competitive NMDA antagonist, (CPP, 0.33, 1.0, 10.0 mg/kg, IP) produced a reduction in discriminability which was linearly related to log dose, but which was only clear at the 10 mg/kg dose. Rate of forgetting was not increased by any dose. Similar results were obtained with a non-competitive antagonist (MK-801, 0.1, 0.33 mg/kg, IP). These data suggest that doses of NMDA receptor channel antagonists sufficient to disrupt hippocampal long-term potentiation and radial arm maze performance will also disrupt delayed conditional discrimination. The effect on delayed conditional discrimination is due to a disruption of stimulus discriminability and not to an increased rate of forgetting. The extent to which these effects relate to the reported changes in hippocampal long-term potentiation and radial arm maze performance remains to be determined.

Animals↗

PubMed1989

Maintenance of long-term potentiation in rat dentate gyrus requires protein synthesis but not messenger RNA synthesis immediately post-tetanization.

The involvement of new protein and messenger ribonucleic acid synthesis in long-term potentiation was studied in the anaesthetized rat dentate gyrus using several inhibitors of protein synthesis (anisomycin, emetine, cycloheximide and puromycin) and an inhibitor of messenger ribonucleic acid synthesis (actinomycin D). When injected for 1 h just prior to tetanization, the four inhibitors of protein synthesis produced a mild reduction of long-term potentiation of the excitatory postsynaptic potential measured 10 min after tetanization. Anisomycin produced a significantly faster decay of long-term potentiation, while the other inhibitors had more moderate effects. Actinomycin D failed to affect long-term potentiation. In a second experiment, the time-dependency of the anisomycin effect was examined. Anisomycin injected immediately after tetanization promoted decay of long-term potentiation, but when injected after a 15-min delay, the drug had no effect. Inhibition of protein synthesis for 4 h prior to tetanization did not have any more effect on long-term potentiation than inhibition for 1 h. In no experiment was long-term potentiation of the population spike affected by drug manipulation. These results suggest that for long-term potentiation of the excitatory postsynaptic potential to be maintained for at least 3 h proteins must be synthesized from already existing messenger ribonucleic acid, and that this synthesis is mostly completed within 15 min after tetanization.

Animals↗