Biomedical subjects

W C Abraham

Publications and source records attributed to W C Abraham.

At least 19 recordsLinked to original sources

PubMed2000

Sequential increase in Egr-1 and AP-1 DNA binding activity in the dentate gyrus following the induction of long-term potentiation.

Establishment of long-term potentiation (LTP) at perforant path synapses is highly correlated with increased expression of Egr and AP-1 transcription factors in rat dentate gyrus granule cells. We have investigated whether increased transcription factor levels are reflected in increased transcription factor activity by assessing Egr and AP-1 DNA binding activity using gel shift assays. LTP produced an increase in binding to the Egr element, which was NMDA receptor-dependent and correlated closely with our previously reported increase in Egr-1 (zif/268) protein levels. Supershift analysis confirmed involvement of Egr-1, but not Egr-2 in the DNA binding activity. AP-1 DNA binding was also rapidly elevated in parallel with protein levels, however, the peak increase in activity was delayed until 4 h, a time point when we have previously shown that only jun-D protein was elevated. These data indicate that binding of Egr-1 and AP-1 to their response elements is increased in two phases. This may result in activation of distinct banks of target genes which contribute to the establishment of persistent LTP.

Animals↗

PubMed2000

Metabotropic glutamate receptors trigger homosynaptic protein synthesis to prolong long-term potentiation.

We investigated the mechanisms by which previous "priming" activation of group I metabotropic glutamate receptors (mGluRs) facilitates the persistence of long-term potentiation (LTP) in area CA1 of rat hippocampal slices. Priming of LTP was elicited by either pharmacological or synaptic activation of mGluRs before a weak tetanic stimulus that normally produced only a rapidly decaying phase of LTP that did not involve protein synthesis or mGluRs. Pharmacological priming of LTP persistence by a selective group I mGluR agonist was blocked by an inhibitor of group I mGluRs and by inhibitors of translation, but not by a transcriptional inhibitor. The same mGluR agonist increased (35)S-methionine incorporation into slice proteins. LTP could also be facilitated using a synaptic stimulation priming protocol, and this effect was similarly blocked by group I mGluR and protein synthesis inhibitors. Furthermore, using a two-pathway protocol, the synaptic priming of LTP was found to be input-specific. To test for the contribution of group I mGluRs and protein synthesis to LTP in nonprimed slices, a longer duration control tetanization protocol was used to elicit a more slowly decaying form of LTP than did the weak tetanus used in the previous experiments. The persistence of the LTP induced by this stronger tetanus was dependent on mGluR activation and protein synthesis but not on transcription. Together, these results suggest that mGluRs couple to nearby protein synthesis machinery to homosynaptically regulate an intermediate phase of LTP dependent on new proteins made from pre-existing mRNA.

Animals↗

PubMed2000

Tyrosine phosphorylation-dependent inhibition of hippocampal synaptic plasticity.

We examined the effects of two protein tyrosine phosphatase inhibitors on the induction of synaptic plasticity in CA1 slices of rat hippocampus. Field potential recordings were made in stratum radiatum in response to stimulation of the Schaffer collateral afferents. Bath application of the tyrosine phosphatase inhibitors sodium orthovanadate or phenylarsine oxide for 30 min had little effect on basal synaptic transmission but blocked the induction of both long-term potentiation (LTP) and homosynaptic long-term depression (LTD). LTP could be partially recovered, and LTD fully recovered, when conditioning stimulation was given in conditions of reduced synaptic inhibition. The block of both forms of synaptic plasticity by the phosphatase inhibitors correlated with a concurrent depression of the N-methyl-D-aspartate (NMDA) receptor-mediated potential, as measured both extracellularly and intracellularly. This depression, which was also induced by peroxyvanadate, required synaptic stimulation to be induced, and was tyrosine kinase-dependent. Our results suggest that tyrosine phosphorylation of as yet unidentified proteins is responsible for a novel activity-dependent depression of NMDA receptor function that inhibits synaptic plasticity.

Animals↗

PubMed1999

Immediate early gene transcription and synaptic modulation.

Long-term changes in gene expression appear to be critical to the formation of memory, but little is known about its stimulus- transcription coupling. Numerous studies in the last decade, by focusing on unraveling this signal transduction pathway, have investigated the potential role of the immediate-early genes in this process. The krox family of immediate-early gene proteins are of particular interest because they may be involved in stabilizing the synaptic modifications that underlie hippocampal long-term potentiation (LTP). A potential upstream mediator of krox induction is cyclic AMP-responsive element binding protein (CREB), a posttranslationally activated transcription factor that has been implicated in numerous memory paradigms. In this study we investigated whether the activation of CREB by phosphorylation may have a role in the development of rat perforant- path-stimulated LTP and associated dentate granule cell krox-24 mRNA expression. Contrary to what was expected, we failed to show any difference in the levels of phosphorylated CREB after LTP or following endogenous synaptic facilitation stimulated by novelty. Using these same model systems we also investigated the protein levels of brain- derived neurotrophic factor (BDNF), another immediate-early gene that is induced following a durable form of LTP. However, BDNF protein was not induced within the hippocampus after LTP and was transiently decreased following novel environmental stimulation.

Animals↗

PubMed1999

A double dissociation within the hippocampus of dopamine D1/D5 receptor and beta-adrenergic receptor contributions to the persistence of long-term potentiation.

We compared the effects of the D1/D5 receptor antagonist SCH-23390 with the beta-adrenergic receptor antagonist propranolol on the persistence of long-term potentiation in the CA1 and dentate gyrus subregions of the hippocampus. In slices, SCH-23390 but not propranolol reduced the persistence of long-term potentiation in area CA1 without affecting its induction. The drugs exerted reverse effects in the dentate gyrus, although in this case the induction of long-term potentiation was also affected by propranolol. The lack of effect of SCH-23390 on the induction and maintenance of long-term potentiation in the dentate gyrus was confirmed in awake animals. The drug also had little or no effect on the expression of inducible transcription factors. In area CA1 of awake animals, SCH-23390 blocked persistence of long-term potentiation beyond 3 h, confirming the results in slices. To rule out a differential release of catecholamines induced by our stimulation protocols between brain areas, we compared the effects of the D1/D5 agonist SKF-38393 with the beta-adrenergic agonist isoproterenol on the persistence of a weakly induced, decremental long-term potentiation in CA1 slices. SKF-38393 but not isoproterenol promoted greater persistence of long-term potentiation over a 2-h period. In contrast, isoproterenol but not SKF-38392 facilitated the induction of long-term potentiation. These data demonstrate that there is a double dissociation of the catecholamine modulation of long-term potentiation between CA1 and the dentate gyrus, suggesting that long-term potentiation in these brain areas may be differentially consolidated according to the animal's behavioural state.

Adrenergic beta-Antagonists↗

PubMed1999

Long-lasting increase in cellular excitability associated with the priming of LTP induction in rat hippocampus.

The mechanisms underlying the facilitation (priming) of long-term potentiation (LTP) by prior activation of metabotropic glutamate receptors (mGluRs) were investigated in area CA1 of rat hippocampal slices. In particular, we focused on whether a long-lasting increase in postsynaptic excitability could account for the facilitated LTP. Administration of the mGluR agonist 1S, 3R-aminocyclopentanedicarboxylic acid (ACPD) produced rapid decreases in the amplitude of both the slow spike afterhyperpolarization (AHP(slow)) and spike frequency adaptation recorded intracellularly from CA1 pyramidal cells. These changes persisted after drug washout, showing only a slow decay over 20 min. ACPD also caused a leftward shift of the field EPSP-population spike relation and an overall increase in population spike amplitude, but this effect was not as persistent as the intracellularly measured alterations in cell excitability. ACPD-treated cells showed increased spike discharges during LTP-inducing tetanic stimulation, and the amplitude of the AHP(slow) was negatively correlated with the degree of initial LTP induction. The beta-adrenergic agonist isoproterenol also caused excitability changes as recorded intracellularly, whereas in extracellular experiments it weakly primed the induction but not the persistence of LTP. ACPD primed both LTP measures. Isoproterenol administration during the tetanus occluded the priming effect of ACPD on initial LTP induction but not its effect on LTP persistence. We conclude that the persistent excitability changes elicited by ACPD contributes to the priming of LTP induction but that other ACPD-triggered mechanisms must account for the facilitated persistence of LTP in the priming paradigm.

Adrenergic beta-Agonists↗

PubMed1998

Biphasic changes in the levels of N-methyl-D-aspartate receptor-2 subunits correlate with the induction and persistence of long-term potentiation.

N-Methyl-D-aspartate glutamate receptors (NMDAR) form ion channels made up of polypeptides from two classes of subunits; NR1 is obligatory for function whereas members of the NR2 class regulate the properties of the channel. Long-term potentiation (LTP) of synaptic transmission is an event largely dependent on NMDAR activation, and is studied as the primary cellular model of memory in the mammalian brain. While there has been a focus on non-NMDARs in mediating the expression of LTP, we report here biochemical evidence for plasticity of the NMDAR that is associated with LTP persistence in awake animals. Following the establishment of LTP in perforant path synapses of the dentate gyrus, we observed a rise in NR2B protein levels 48 h post-tetanus which was dependent upon activation of NMDARs during the tetanization, and which strongly correlated with the degree of LTP measured at this time-point. We also observed a transient increase in both NR2B and NR2A protein levels 20 min post-tetanus that returned to control levels by 4 h. These early increases were not observed in anaesthetized animals which do not sustain persistent LTP. Our data demonstrate a marked plasticity of NMDAR subunit expression, which may affect LTP persistence, as well as the subsequent ability to induce LTP at previously activated synapses.

Animals↗

PubMed1998

Synaptic activity-dependent modulation of mitochondrial gene expression in the rat hippocampus.

In order to identify genes that may underlie the maintenance of long-term potentiation (LTP) at perforant path synapses, complementary DNA libraries were synthesised from dentate gyrus total RNA extracts prepared 48 h after the induction of LTP and from control dentate gyrus extracts. Through differential screening of the LTP library we have identified the mitochondrial 12S rRNA (mt12SrRNA) as a transcript that was elevated at this late time. Northern blot analyses showed that the elevation in mt12SrRNA expression began around 8 h and persisted for at least 2 weeks post-tetanus. We then examined the expression patterns of other mitochondrially-encoded genes and demonstrated a similar elevation in their expression. mt12SrRNA levels were also elevated in other hippocampal regions, including areas CA3 and CA1 and were elevated following low-frequency stimulation or in the presence of an N-methyl-D-aspartate receptor antagonist where induction of LTP was precluded. Taken together, these observations suggest that a long-lasting up-regulation of energy production may be triggered by synaptic activity and this activity need not be of sufficient strength to induce LTP, but may be related to the induction of a metaplastic state.

Animals↗

PubMed1998

Effects of endothelin-1 on hippocampal synaptic plasticity.

We examined the effects of puff application of endothelin (ET)-1 on the induction of long-term potentiation (LTP) and heterosynaptic long-term depression (LTD) in hippocampal CA1 slices. ET-1 applied 2 min prior to tetanus blocked the induction of LTP, but facilitated the induction of heterosynaptic LTD. These ET-1 effects on synaptic plasticity were dose-dependent, and not due to a generalized depression of baseline responses. ET-1 did not alter NMDA receptor-mediated responses. These data provide the first evidence that endothelin modulates activity-dependent synaptic plasticity, and the potency of these effects suggests that endogenous ET-1 may play an important role in regulating memory storage processes.

Animals↗

PubMed1998

Priming of long-term potentiation induced by activation of metabotropic glutamate receptors coupled to phospholipase C.

Activation of metabotropic glutamate receptors (mGluRs) with 1-aminocyclopentane-1S,3R-dicarboxylic acid 20 min prior to tetanus facilitates, or "primes," subsequent induction of long-term potentiation (LTP; Cohen and Abraham, J Neurophysiol 1996;76:953-962). In the present study, we investigated the receptor specificity and associated second messenger pathways involved in the mGluR priming effect by using field potentials recorded from area CA1 of rat hippocampal slices. In controls, mild theta-burst or high-frequency (100 Hz) stimulation induced 16% and 21% LTP, respectively. A 10-min application of the group I mGluR agonist 3,5-dihydroxyphenylglycine (DHPG) caused a transient depression of synaptic responses but a significant enhancement of subsequent LTP for both tetanus protocols (45% and 41% LTP, respectively). Maximal LTP, induced by stronger tetanization protocols, was not enhanced by DHPG, nor was mild LTP facilitated by post-tetanic application of DHPG. Priming with agonists selective for group II or III mGluRs had no effect on LTP. The mGluR antagonists L-2-amino-3-phosphonopropionic acid and 1-aminoindan-1,5-dicarboxylic acid inhibited the LTP facilitatory effect of DHPG but not the transient response depression, whereas alpha-methyl-4-carboxyphenylglycine produced the opposite effects. Priming with N-methyl-D-aspartate or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid did not facilitate LTP induction. Prior activation of muscarinic acetylcholine receptors produced at best a weak priming effect. Inhibition of phospholipase C by U-73122 completely abolished the priming of LTP by DHPG. We conclude that mGluR priming of LTP results from biochemical cascades triggered by activation of phospholipase C coupled to group I mGluRs.

Animals↗

PubMed1997

Induction and reversal of long-term potentiation by repeated high-frequency stimulation in rat hippocampal slices.

Field potential recordings were made from area CA1 of hippocampal slices from young adult rats to study the effects of repeated tetanic stimulation on the development of LTP. Stimulation was applied to the Schaffer collateral afferents, and field excitatory postsynaptic potentials were recorded in stratum radiatum. Theta-burst stimulation (TBS) resulted in variable amounts of long-term potentiation (LTP), depending on how many trains of stimulation were delivered. Peak amounts of LTP occurred after 8-16 trains of TBS, but virtually no LTP occurred after 24 or 32 trains of TBS. There was thus an inverted U-shaped relation between the amount of TBS and the degree of LTP. The temporal spacing of TBS trains was important for observing the lack of LTP after 32 trains ("over-stimulation"). If the trains were grouped into blocks of 8, with 10 min between blocks, LTP occurred normally. This finding suggests that a time-dependent LTP reversal process was occurring during the massed presentation of TBS trains. Over-stimulation inhibited for 60-90 min the subsequent induction of LTP by a normally efficient LTP-inducing protocol. This effect was input specific and dependent on activation of N-methyl-D-aspartate (NMDA) receptors. Lowering extracellular [Ca2+] from 2.5 to 2.0 mM, or adding the L-type calcium channel antagonist nimodipine, had only a small protective effect on the lack of LTP induced by 32 trains of TBS. Addition of an NMDA receptor antagonist to the bath solution shortly after the beginning of the over-stimulation protocol gave significantly more protection. Administration of an adenosine (A1) receptor antagonist during over-stimulation permitted robust LTP to occur, indicating that A1 receptor activation during TBS contributes to the depotentiation process. These findings confirm previous findings in the dentate gyrus that repeated afferent tetanization within a narrow time frame can lead to a loss or reversal of LTP. Activation of adenosine receptors appears to trigger this effect.

Adenosine↗

PubMed1997

Sequence-independent effects of phosphorothiolated oligonucleotides on synaptic transmission and excitability in the hippocampus in vivo.

Antisense oligodeoxynucleotides (ODNs) have the potential to be a powerful tool for regulating gene expression and mRNA translation in spatially and temporally restricted domains. Prior to investigating the effects of antisense ODNs on hippocampal long-term potentiation, we investigated whether there are any non-specific effects of ODNs on perforant path synaptic transmission in the dentate gyrus of both pentobarbital-anaesthetized and awake, freely moving rats. Single injections of phosphorothioated antisense ODNs (4 nmol) to the immediate early gene zif/268 caused a rapid (within minutes) and long-lasting (>24 hr) profound depression of the perforant path evoked field potentials. This depressive effect was due to the phosphorothioate modification since a depression was not seen with unmodified antisense ODNs, relative to saline controls. Furthermore, the effect was not sequence-specific since modified sense ODNs caused the same degree of depression. The depression caused by the modified antisense ODNs was dose-dependent and specific to synaptic transmission, since antidromic population spikes elicited by mossy fibre stimulation were relatively unaffected compared to the orthodromic responses. A second unexpected side-effect of the modified ODNs was cellular hyperexcitability, such that bursts of epileptiform spikes in the EEG occurred both spontaneously and as a result of synaptic stimulation. While the mechanism of the synaptic depression remains unknown, these results indicate that phosphorothioate-modified ODNs exert profound non-specific effects on synaptic transmission in the hippocampus, that have the potential to seriously compromise any corresponding behavioural or electrophysiological studies.

Animals↗

PubMed1997

TrkB expression in dentate granule cells is associated with a late phase of long-term potentiation.

Recent studies have demonstrated that the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are induced in hippocampal neurons following the induction of long-term potentiation (LTP), a model of memory, and that BDNF and NT-3 (but not NGF) can induce LTP-like increases in synaptic efficacy. Receptors for these neurotrophins have been cloned and characterized and we investigated whether LTP alters the expression of two neurotrophin receptors, trkB (BDNF receptor) and trkC (NT-3 receptor) in dentate granule neurons of the hippocampus using in situ hybridization analysis. Results show that trkB is strongly induced in these neurons in an N-methyl-D-aspartate (NMDA) receptor-dependent manner. Moreover, the induction of trkB and trkC mRNAs was attenuated by sodium pentobarbital, which interferes with the durability of LTP. Low-frequency stimulation of the perforant path had no effect on trkB mRNA levels but significantly reduced trkC mRNA in dentate granule cells. Thus, both BDNF and its receptor trkB are induced in granule cells by stimulation that produces durable LTP, suggesting that this neurotrophin and its receptor play an important role in memory formation and may be suitable targets for the development of cognitive-enhancing drugs in the treatment of diseases, such as Alzheimer's.

Animals↗

PubMed1997

Metaplasticity: a new vista across the field of synaptic plasticity.

Over the past 20 years there has been an increasing understanding of the properties and mechanisms underlying long-term potentiation (LTP) and long-term depression (LTD) of synaptic efficacy, putative learning and memory mechanisms in the mammalian brain. More recently, however, it has become apparent that synaptic activity can also elicit persistent neuronal responses not manifest as changes in synaptic strength. Some of these changes may nonetheless modify the ability of synapses to undergo strength changes in response to subsequent episodes of synaptic activity. This kind of activity-dependent modulatory plasticity we have termed "metaplasticity". Metaplasticity has been observed physiologically as an inhibition of LTP and concomitant facilitation of LTD by prior N-methyl-D-aspartate receptor activation or, conversely, a facilitation of LTP induction by prior metabotropic glutamate receptor activation. The examples of metaplasticity described to date are input specific, and last as long as several hours. The mechanisms underlying such phenomena remain to be fully characterized, although some likely possibilities are an altered N-methyl-D-aspartate receptor function, altered calcium buffering, altered states of kinases or phosphatases, and a priming of protein synthesis machinery. While some details vary, experimentally observed metaplasticity bears some similarity to the "sliding threshold" feature of the Bienenstock, Cooper and Munro model of experience-dependent synaptic plasticity. Metaplasticity may serve several functions including (1) providing a way for synapses to integrate a response across temporally spaced episodes of synaptic activity and (2) keeping synapses within a dynamic functional range, and thus preventing them from entering states of saturated LTP or LTD.

Animals↗

PubMed1997

Glucocorticoid receptor activation lowers the threshold for NMDA-receptor-dependent homosynaptic long-term depression in the hippocampus through activation of voltage-dependent calcium channels.

The effects of the glucocorticoid receptor agonist RU-28362 on homosynaptic long-term depression (LTD) were examined in hippocampal slices obtained from adrenal-intact adult male rats. Field excitatory postsynaptic potentials were evoked by stimulation of the Schaffer collateral/commissural pathway and recorded in stratum radiatum of area CA1. Low-frequency stimulation (LFS) was delivered at LTD threshold (2 bouts of 600 pulses, 1 Hz, at baseline stimulation intensity). LFS of the Schaffer collaterals did not produce significant homosynaptic LTD in control slices. However, identical conditioning in the presence of the glucocorticoid receptor agonist RU-28362 (10 microM) produced a robust LTD, which was blocked by the selective glucocorticoid antagonist RU-38486. The LTD induced by glucocorticoid receptor activation was dependent on N-methyl-D-aspartate (NMDA) receptor activity, because the specific NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) blocked the facilitation. However, the facilitation of LTD was not due to a potentiation of the isolated NMDA receptor potential by RU-28362. The facilitation of LTD by RU-28362 was also blocked by coincubation of the L-type voltage-dependent calcium channel (VDCC) antagonist nimodipine. Selective activation of the L-type VDCCs by the agonist Bay K 8644 also facilitated LTD induction. Both nimodipine and D-AP5 were effective in blocking the facilitation of LTD by Bay K 8644. These results indicate that L-type VDCCs can contribute to NMDA-receptor-dependent LTD induction.

Androstanols↗

PubMed1996

Low-frequency stimulation does not readily cause long-term depression or depotentiation in the dentate gyrus of awake rats.

The ability of low-frequency stimulation (LFS) to induce either long-term depression (LTD) or depotentiation was assessed for perforant path synapses in the dentate gyrus of awake, adult rats. Neither LFS at 1 Hz (100 or 900 pulses) nor LFS at 3 Hz (900 pulses) was sufficient to produce either LTD or depotentiation. LFS at 3 Hz did produce a transient response depression of previously potentiated synapses, but this lasted less than 24 h and was secondary to seizure-like afterdischarges. We conclude that the LFS protocols so effective at eliciting LTD and depotentiation in area CA1 are ineffective for perforant path synapses in the dentate gyrus.

Animals↗

PubMed1996

Bidirectional modification of CA1 synapses in the adult hippocampus in vivo.

Memories are believed to be stored by synaptic modifications. One type of activity-dependent synaptic modification, long-term potentiation (LTP), has received considerable attention as a possible memory mechanism, particularly in hippocampus. However, use-dependent decreases in synaptic strength can store information as well. A form of homosynaptic long-term depression (LTD) has been described and widely studied in the CA1 region of the developing hippocampus in vitro. However, the relevance of this model of LTD to memory has been questioned because of failures to replicate it in the adult brain in vitro and, more recently, in vivo. Here we re-examine this important issue and find that homosynaptic LTD can in fact be elicited in the adult hippocampus in vivo, that it has all the properties described in immature CA1 in vitro, and that LTD and LTP are reversible modifications of the same Schaffer collateral synapses. Thus homosynaptic LTD is not peculiar to brain slices, nor is it only of developmental significance. Rather, out data suggest that the mechanisms of LTD and LTD may be equal partners in the mneumonic operations of hippocampal neural networks.

Animals↗

PubMed1996

LTD: many means to how many ends?

Several forms of long-term synaptic depression (LTD) have been identified in the hippocampus. Although these LTDs differ in their methods of induction, it remains unclear whether they converge upon some final common mechanism(s) of expression. In the present paper we review critical aspects of heterosynaptic and homosynaptic LTD induction and consider those findings relevant to the expression of each. In addition, we suggest several experimental approaches which may be of benefit in addressing the commonality of LTD expression mechanisms.

Animals↗