Novel expression mechanism for synaptic potentiation: alignment of presynaptic release site and postsynaptic receptor

A combination of experimental and modeling approaches was used to study cellular-molecular mechanisms underlying the expression of short-term potentiation (STP) and long-term potentiation (LTP) of glutamatergic synaptic transmission in the hippocampal slice. Electrophysiological recordings from dentate granule cells revealed that high-frequency stimulation of perforant path afferents induced a robust STP and LTP of both (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) receptor-mediated synaptic responses. However, the decay time constant for STP of the AMPA receptor-mediated excitatory postsynaptic potential was approximately 6 min, whereas the decay time constant for STP of the NMDA receptor-mediated excitatory postsynaptic potential was only 1 min. In addition, focal application of agonists during the expression of STP revealed that the magnitude of conductance change elicited by NMDA application was significantly enhanced, whereas the magnitude of conductance change elicited by application of AMPA remained constant. These findings are most consistent with a postsynaptic mechanism of STP and LTP. Different putative mechanisms were evaluated formally using a computational model that included diffusion of glutamate within the synaptic cleft, different kinetic properties of AMPA and NMDA receptor/channels, and geometric relations between presynaptic release sites and postsynaptic receptor/channels. Simulation results revealed that the only hypothesis consistent with experimental data is that STP and LTP reflect a relocation of AMPA receptor/channels in the postsynaptic membrane such that they become more closely "aligned" with presynaptic release sites. The same mechanism cannot account for STP or LTP of NMDA receptor-mediated responses; instead, potentiation of the NMDA receptor subtype is most consistent with an increase in receptor sensitivity or number.     

Ethanol effects on synaptic neurotransmission and tetanus-induced synaptic plasticity in hippocampal slices of chronic in vivo lead-exposed adult rats

The interaction of chronic in vivo lead exposure and acute in vitro ethanol treatment on synaptic neurotransmission and plasticity were studied using extracellular electrophysiological techniques in CA1 region of hippocampal brain slices from adult rats. Neither chronic lead exposure nor acute ethanol treatment had any significant effect on field excitatory postsynaptic potentials (EPSPs). In vivo lead exposure enhanced short-term potentiation (STP, potentiation that decays within 30 min) by 21% shortly after 'weak' tetanus, but had no effect on long-term potentiation (LTP, sustained at least 1 h). In vitro bath application of 60 mM ethanol inhibited STP by 35% and blocked LTP induced by 'weak' tetanus in slices from Pb exposed rats (500 ppm lead acetate, 56-70 days), while having no effect on STP or LTP in slices from control counterpart Na-exposed rats (pair-fed 216 ppm sodium acetate). In contrast, 'strong'-tetanus-induced LTP was abolished in Pb-exposed slices, and 60 mM ethanol slightly inhibited STP and blocked LTP in slices from Na-exposed rats. These differences could not be explained by differences in ethanol inhibition of NMDA-mediated field EPSPs because they were similarly reduced in slices from Na-exposed (30%) and Pb-exposed (25%) rats. These findings suggest that the strength of the tetanus used determines whether or not synaptic plasticity is blocked by either chronic lead exposure or acute ethanol treatment, and that even in adult rats, hippocampal synaptic LTP can be compromised by combined exposure to ethanol and lead. More importantly, these findings suggest the consequences of combined lead exposure and alcohol abuse in the adult human population may not be fully recognized yet.     

Differing mechanisms of expression for short- and long-term potentiation

Long-term potentiation (LTP) is a use-dependent form of synaptic plasticity that is of great interest as a cellular mechanism that may contribute to memory storage. It is the sustained phase of population excitatory postsynaptic potential induced by high-frequency stimulation (HFS). HFS can also induce short-term potentiation (STP), a decremental potentiation lasting approximately 15 min. It has been unclear whether STP is simply a reversible form of LTP elicited by subthreshold stimuli or whether it is an independently expressed form of synaptic plasticity. We have attempted to clarify the relationship between LTP and STP in the extracellular recording technique in area CA1 of the adult rat hippocampal slice preparation to test four predictions of the hypothesis that LTP and STP are expressed via the same mechanism. First, occluding LTP expression should block STP expression. Saturating LTP under six different conditions, however, did not occlude STP expression. Second, occluding STP expression should occlude LTP expression. The partial or full occlusion of STP by two maneuvers (increasing the stimulus intensity used for HFS or applying 3-isobutyl-1-methylxanthine), however, did not occlude LTP expression. Third, LTP increases and decreases paired-pulse facilitation (PPF), and STP should have the same effect. STP did not change PFF, however. The first three results, then, suggest that STP and LTP are expressed via different mechanisms. Fourth, STP should be maximal near the LTP induction threshold, and then decrease above it. Surprisingly, STP was maximal at or very close to the LTP induction threshold, but it did not decrease above this threshold. This relationship suggests the possibility that STP and LTP share an induction step(s). What is the function of the independently expressed STP? We find that LTP can be induced by two HFSs, each of which is subthreshold for LTP, if the second is given during STP from the first. This suggests that STP can temporarily lower the LTP induction threshold. Three lines of evidence, then, suggest that STP and LTP may be expressed via different mechanisms; however, the proximity of STP saturation to LTP induction suggests that they may share an induction step(s). STP may also have the very important function of temporarily lowering the LTP induction threshold. Finally, these data suggestion caution in interpreting LTP data obtained <20-30 min after HFS, because they may be contaminated by STP, which appears to have different underlying mechanisms.     

G2 cell cycle arrest and apoptosis are induced in Burkitt''s lymphoma cells by the anticancer agent oracin

The gamma isoform of protein kinase C (gamma-PKC) activity is elevated and learning is superior in the inbred C57BL/6 mouse when compared to the DBA/2 mouse strain. Given the proposed link between PKC and long-term potentiation (LTP) on the one hand and PKC and learning on the other, it was predicted that LTP persistence would be greater in C57BL/6 mouse. When suprathreshold levels of tetanic stimulation were used, similar persistent LTP was observed in both C57BL/6 and DBA/2 strains. However, when tetanus was at threshold, the response in DBA/2 mice decayed to baseline in 30 min, similar to short-term potentiation (STP). Using this same paradigm with C57BL/6 mice, LTP persisted for 4 h, the longest time tested. The time course of the results parallels those observed in rat when phorbol ester, a potent PKC activator, converts STP to LTP. The present findings thus confirm the predicted difference between the two mouse strains. Moreover, the present findings are consistent with a role for gamma-PKC in LTP. Since such results call attention to the need for gamma-PKC interventive procedures, the relative utility of current PKC inhibitors, null mutants and antisense methods are discussed.     

In vivo activity-dependent plasticity at cortico-striatal connections: evidence for physiological long-term potentiation

The purpose of the present study was to investigate in vivo the activity-dependent plasticity of glutamatergic cortico-striatal synapses. Electrical stimuli were applied in the facial motor cortex and intracellular recordings were performed in the ipsilateral striatal projection field of this cortical area. Recorded cells exhibited the typical intrinsic membrane properties of striatal output neurons and were identified morphologically as medium spiny type I neurons. Subthreshold cortical tetanization produced either short-term posttetanic potentiation or short-term depression of cortically-evoked excitatory postsynaptic potentials. When coupled with a postsynaptic depolarization leading the membrane potential to a suprathreshold level, the tetanus induced long-term potentiation (LTP) of cortico-striatal synaptic transmission. Induction of striatal LTP was prevented by intracellular injection of a calcium chelator suggesting that this synaptic plasticity involves an increase of postsynaptic free calcium concentration. Contrasting with previous in vitro studies our findings demonstrate that LTP constitutes the normal form of use-dependent plasticity at cortico-striatal synapses. Since excitation of striatal neurons produces a disinhibition of premotor networks, LTP at excitatory striatal inputs should favor the initiation of movements and therefore could be critical for the functions of basal ganglia in motor learning.     

Concurrent blockade of beta-adrenergic and muscarinic receptors suppresses synergistically long-term potentiation of population spikes in the rat hippocampal CA1 region

The muscarinic acetylcholine receptor antagonist scopolamine, but not the beta-adrenoceptor antagonist propranolol or atenolol, suppressed tetanus-induced long-term potentiation (LTP) of population spikes in the rat hippocampal CA1 region. When scopolamine was coapplied with propranolol or atenolol, a synergistic effect in preventing LTP generation was observed. On the other hand, the coapplication of scopolamine and atenolol failed to affect tetanus-induced LTP of field EPSP. These findings suggest that cooperative mechanisms via muscarinic and beta-adrenergic receptor activation might contribute to LTP induction in terms of the EPSP-spike potentiation, i.e., an increase in the excitability of hippocampal CA1 pyramidal cells after tetanic stimulation, but are independent of the tetanus-evoked potentiation of a synaptic component.     

Is hypothalamic GABA involved in immune function in relation to dietary protein during aging?

Hypothalamic GABAergic activity and immune response in spleen were not significantly changed with the increase of age from 3 to 6 months in adult male albino rats. Further increase of age from 6 to 9 months increase the GABAergic activity and decreased the cell viability in spleen without any change in its T-lymphocyte cytotoxicity. Consumption of low protein diet (LPD) for a short-term period (STP; 7 consecutive days) increased the hypothalamic GABAergic activity without changing the immune response in 3 months old rats. When supplemented for a long-term period (LTP; 30 consecutive days) to 3 months old rats, a reduction of hypothalamic GABAergic activity and the immune response was observed. Intake of high protein diet (HPD) for both STP and LTP increased the GABAergic activity and immune response, but the increase of GABAergic activity in hypothalamus under STP was greater than that observed under LTP. In 6 months old rats consumption of LPD for STP reduced the GABAergic activity without any alteration of its immune response. Long-term supplementation of this LPD to the same age group increased GABAergic activity and the mitotic activity of spleen cells without any alteration of the functional activity of the T-cells in spleen. Consumption of HPD for STP failed to produce any change in hypothalamic GABAergic activity and the immune response of 6 months old rats. Supplementation of HPD for LTP reduced the hypothalamic GABAergic activity and the immune response of the same age group. The reduction in hypothalamic GABAergic activity without any change in the immune response was observed following the supplementation of low protein diet to 9 months old rat for STP. Intake of the LPD for LTP also reduced the hypothalamic GABAergic activity and the mitotic activity of the spleen cells without any alteration of the functional activity of the T-cells in spleen of 9 months old rats. Supplementation of HPD for STP to this aged rat, on the other hand, failed to produced any change in hypothalamic GABAergic activity and the immune response. Intake of HPD for LTP by this aged rats increased the hypothalamic GABAergic activity along with the immune response. The results of this study, thus, suggest that hypothalamic GABAergic activity during aging is an index of immune response and it is modulated following the short- and long-term consumption of protein poor and protein rich diet.     

The selective neuronal NO synthase inhibitor 7-nitro-indazole blocks both long-term potentiation and depotentiation of field EPSPs in rat hippocampal CA1 in vivo

The membrane-permeant gas NO is a putative intercellular messenger that has been proposed on the basis of previous in vitro studies to be involved in synaptic plasticity, especially the induction of long-term potentiation (LTP) of excitatory synaptic transmission in the hippocampus and cortex. In the present study, the role of NO in synaptic plasticity has been investigated in vivo. In particular, the action of the novel and selective neuronal NO synthase (nNOS) inhibitor 7-nitro-indazole (7-NI) has been investigated on the induction of LTP and depotentiation (DP) of field EPSPs in CA1 of the hippocampus in vivo. Unlike previously studied nonselective NOS inhibitors, 7-NI does not increase arterial blood pressure. In vehicle-injected rats, high-frequency stimulation consisting of a series of trains at 200 Hz induced LTP. However, LTP induction was strongly inhibited in 7-NI (30 mg/kg, i.p.)-treated animals. The inhibitory effect of 7-NI on the induction of LTP was prevented by pretreatment with L-arginine, the substrate amino acid used by NOS. In control animals, low-frequency stimulation consisting of 900 stimuli at 10 Hz induced DP of previously established LTP, whereas in 7-HI-treated animals only a short-term depression was induced. This effect of 7-NI also was prevented by D-arginine. The LTP and DP induced in control animals in this study were NMDA receptor-dependent, the NMDA receptor antagonist 3-(R,S)-2-carboxypiperazin-4-yl-propyl-1- phosphonic acid inhibiting the induction of both forms of synaptic plasticity. The present experiments are the first to demonstrate that an NOS inhibitor blocks the induction of the synaptic component of LTP and DP in vivo and, therefore, these results strengthen evidence that the production of NO is necessary for the induction of LTP and DP.     

Chronic in vivo morphine administration facilitates primed-bursts-induced long-term potentiation of Schaffer collateral-CA1 synapses in hippocampal slices in vitro

In this study, the effects of chronic morphine administration (20-30 days) on long-term potentiation (LTP) were investigated at the Schaffer collateral-CA1 pyramidal cell synapses of the rat hippocampal slices. Orthodromic population spike (OPS) amplitude and delay (peak latency) were measured as indices of increase in synaptic efficacy. The amounts of LTP of OPS delay and LTP of OPS amplitude were higher in slices from dependent rats. Perfusion of slices from control and dependent rats with morphine containing ACSF and delivering tetanic stimulation, showed that short-term presence of morphine could not mimic the LTP enhancing effects of chronic morphine administration, however, attenuated the amount of LTP of OPS amplitude in slices of dependent rats. This study supports the hypothesis that the susceptibility of CA1 synapses to plastic changes increases by chronic, not acute exposure to morphine and suggests that a withdrawal phenomenon might be an underlying mechanism for the observed augmented LTP of OPS amplitude in slices of dependent rats.     

Synaptic transmission and hippocampal long-term potentiation in olfactory cyclic nucleotide-gated channel type 1 null mouse

Field potential recording was used to investigate properties of synaptic transmission and long-term potentiation (LTP) at Schaffer collateral-CA1 synapses in both hippocampal slices of mutant mice in which the alpha-subunit of the olfactory cyclic nucleotide-gated channel (alpha3/OCNC)1 was rendered null and also in slices prepared from their wild-type (Wt) littermates. Several measures of basal synaptic transmission were unaltered in the OCNC1 knockout (KO), including maximum field excitatory postsynaptic potential (fEPSP) slope, maximum fEPSP and fiber volley amplitude, and the function relating fiber volley amplitude to fEPSP slope and paired-pulse facilitation. When a high-frequency stimulation protocol was used to induce LTP, similar responses were seen in both groups [KO: 1 min, 299 +/- 50% (mean +/- SE), 60 min, 123 +/- 10%; Wt: 1 min, 287 +/- 63%; 60 min, 132 +/- 19%). However, on theta-burst stimulation, the initial amplitude of LTP was smaller (1 min after induction, 147 +/- 16% of baseline) and the response decayed faster in the OCNC1 KO (60 min, 127 +/- 18%) than in Wt (1 min, 200 +/- 14%; 60 min, 169 +/- 19%). Analysis of waveforms evoked by LTP-inducing tetanic stimuli revealed a similar difference between groups. The development of potentiation throughout the tetanic stimulus was similar in OCNC1 KO and Wt mice when high-frequency stimulation was used, but OCNC1 KO mice showed a significant decrease when compared with Wt mice receiving theta-burst stimulation. These results suggest that activation of cyclic nucleotide-gated channels may contribute to the induction of LTP by weaker, more physiological stimuli, possibly via Ca2+ influx.     

N-methyl-D-aspartate receptors are indispensable for the formation of long-term potentiation in the rat suprachiasmatic nucleus in vitro

Optic nerve (ON) stimulation caused a postsynaptic field potential in the suprachiasmatic nucleus (SCN) of rat hypothalamic slices. The postsynaptic field potential was suppressed by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA receptor antagonist, in a concentration-dependent manner, but not affected by D-amino-5-phosphonovaleric acid (APV), a competitive NMDA receptor antagonist. Tetanic stimulation to the ON induced long-term potentiation (LTP) in the SCN. Application of APV at 50 microM inhibited the induction of LTP by tetanic stimulation but CNQX at lower dose (5 microM) didn't inhibit it. These results suggest that NMDA receptors are indispensable for the induction of LTP after tetanic stimulation.     

Anoxic LTP is mediated by the redox modulatory site of the NMDA receptor

1. The effects of redox reagents, 5,5'-dithiobis-2-nitrobenzoic acid (DTNB) and tris(carboxyethyl)phosphine (TCEP), on anoxia-induced long-term potentiation (LTP) were investigated in CA1 hippocampal neurons using extracellular recording techniques. Experiments were performed in the presence of 0.1 mM MgCl2 and 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) to pharmacologically isolate N-methyl-D-aspartate (NMDA) receptor-mediated responses. 2. DTNB (200 microM), a thiol oxidizing reagent, reduces by 52 +/- 9% (mean +/- SE) (n = 9/9) NMDA-receptor field potentials evoked by electrical stimulation of Schaffer collaterals and this effect could not be reversed by extensive washing. Nearly the same reduction of the initial response was obtained with different concentrations of DTNB (100 and 500 microM), but the time required to reach the maximal inhibition was concentration-dependent. 3. In keeping with an earlier study oxygen and glucose deprivation for 2-3 min induced a long-term potentiation (LTP) of the NMDA receptor response (+65 +/- 16%, n = 4/6). This potentiation was reversed by DTNB (100-500 microM) (-47 +/- 18%; n = 4/4) and the initial LTP could not be restored upon extensive washing of the drug. 4. TCEP (200 microM), a reagent which reduces S-S bond, amplified the electrically evoked NMDA-receptor EPSP (+27 +/- 12%; n = 3). In addition, TCEP (200 microM), nearly completely reversed the effect of DTNB (200 microM) on anoxia-induced LTP (+56 +/- 19%; n = 3/3). Preliminary results also indicate that TCEP occlude anoxic-LTP (n = 3/4). 5. Following DTNB (200 microM) treatment, oxygen and glucose deprivation did not generate anoxic LTP and extensive washing did not restore a potentiated NMDA field potential. 6. These observations strongly suggest that the redox site of the NMDA receptor is involved in the induction and the maintenance of the anoxic LTP of the NMDA receptor-mediated response in CA1.     

Is the prion structure solved?

We report here on the current knowledge on the nature of the scrapie agent or prion. Several lines of evidence suggest that the abnormal isoform of prion protein (PrP) is crucial for scrapie infectivity while evidence that PrP is also a part of the entire particle of the scrapie agent (prion) is much weaker. There is no doubt, however, that conformational changes (transitions from alpha-helical into beta-pleated structures) of PrP underlay scrapie pathogenesis. In view of the notorious puzzling nature of the scrapie agent, the electron microscopic search for the ultrastructural correlate of it is still warranted. Thus, we discuss the nature of tubulovesicular structures (TVS), the only diseases-specific particles known so far and the association between TVS and PrP fibrils which was recently discovered.     

When are class I metabotropic glutamate receptors necessary for long-term potentiation?

The involvement of metabotropic glutamate receptors (mGluRs) in hippocampal long-term potentiation (LTP) is a matter of controversial debate. Using [Ca2+]i measurements by confocal laser scanning microscopy and field recordings of EPSPs (fEPSPs) in the hippocampal CA1-region, we found that the efficacy of the broad-spectrum mGluR-antagonist (S)-alpha-methyl-4-carboxyphenylglycine (MCPG) and of (S)-4-carboxy-phenylglycine (4-CPG), a selective antagonist at class I mGluRs, in LTP is contingent on the tetanization strength and the resulting [Ca2+]i response. As indicated by experiments in which we blocked voltage-dependent calcium channels (VDCCs) and intracellular Ca2+ stores (ICSs), the functional significance of class I mGluRs in LTP is confined to certain types of potentiation, which are induced by weak tetanization protocols and require the release of Ca2+ from ICSs for induction. During strong tetanic stimulation, this Ca2+ source is functionally bypassed by activating VDCCs.     

Transgenic mice with cerebral expression of human immunodeficiency virus type-1 coat protein gp120 show divergent changes in short- and long-term potentiation in CA1 hippocampus

The human immunodeficiency virus type-1 envelope glycoprotein gp120 is shed from the virus and from infected cells and thus can diffuse and interact with a variety of central nervous system cells. Transgenic mice constitutively expressing glial fibrillary acidic protein-driven gp120 from brain astrocytes display neuronal and glial changes resembling abnormalities in human immunodeficiency virus type-1-infected human brains. To assess the neurophysiology of these transgenic mice and determine whether gp120 expression impairs synaptic plasticity, we examined CA1 population excitatory postsynaptic potentials in hippocampal slices from transgenic mice and from non-transgenic controls, using a double-blind protocol. Compared with slices from non-transgenic littermate controls, slices from gp120 transgenic mice showed four significant alterations: (i) increased mean slopes of normalized population excitatory postsynaptic potentials; (ii) larger paired-pulse facilitation after induction of long-term potentiation at 50 ms interpulse intervals; (iii) markedly elevated short-term potentiation after 10 and 20 shocks at 100 Hz; and (iv) a significant reduction in the magnitude of CA1 long-term potentiation. In slices from transgenic mice expressing Escherichia coli beta-galactosidase from the same promoter, paired-pulse facilitation and long-term potentiation were normal. These results indicate that brain slice preparations from gp120 transgenic mice can be used to assess pathophysiological effects of gp120 on neuronal networks. Because short-term potentiation involves presynaptic mechanisms, our results suggest that gp120 expression in these mice enhances either presynaptic glutamate release or postsynaptic glutamate receptor function, or both. These changes could lead to increased Ca2+ influx, thereby contributing to neuronal dysfunction and injury. As long-term potentiation is a cellular model of learning and memory, our results may be relevant to memory (cognitive) impairments seen in patients with AIDS.     

Bidirectional associative plasticity of unitary CA3-CA1 EPSPs in the rat hippocampus in vitro

Associative long-term potentiation (LTP) and depression of compound and unitary CA3-CA excitatory postsynaptic potentials (EPSPs) were investigated in rat hippocampal slice cultures. The induction of LTP with synchronous pairing of synaptic activation and postsynaptic depolarization resulted in an increase in the amplitude of EPSPs to the same absolute level, regardless of whether the input was naive or had been previously depressed by asynchronous pairing of pre- and postsynaptic activity. Saturated LTP of compound and unitary EPSPs was reversed by asynchronous pairing and could be reinduced by synchronous pairing. The likelihood that an action potential in a presynaptic CA3 cell failed to trigger an unitary EPSP in a postsynaptic CA1 cell decreased after induction of associative potentiation and increased after induction of associative depotentiation. These changes in the rate of transmission failures were accompanied by large changes in the amplitude of nonfailure EPSPs. We conclude that the same CA3-CA1 synapses can alternatively undergo associative potentiation and depression, perhaps through opposite changes in a single expression mechanism.     

Time-dependent reversal of long-term potentiation by an integrin antagonist

The integrin antagonist Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) was applied by local ejection to one of two recording sites in hippocampal slices at various times before and after long-term potentiation (LTP) was induced at both sites with theta burst stimulation. Applications 10 min before, immediately after, and 10 min after induction caused LTP at the experimental site to decay steadily relative to that at the within-slice control site. However, application at 25 min or more after induction had no detectable effect on potentiation. Similar results were obtained when the integrin antagonist was perfused into the slice rather than applied locally. The time period after induction during which GRGDSP interfered with LTP consolidation corresponds to that during which LTP is susceptible to reversal by low-frequency afferent stimulation and newly formed memories are vulnerable to various disruptive treatments. Comparable experiments using a peptide that blocks an extracellular binding site of neural cell adhesion molecules (NCAMs) did not yield time-dependent reversal of LTP; i.e., an antagonist that interacts with the fourth immunoglobulin-like domain reduced LTP when applied before induction but not afterward. Moreover, LTP formation occurred normally in the presence of an antibody against the fibronectin repeat domain of NCAM. These results suggest that integrin activation and signaling occurring over several minutes after LTP induction are necessary for stabilizing synaptic potentiation and by inference may be required for the conversion of new memories into a not readily disrupted state.     

Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons

Hippocampal long-term potentiation (LTP) is thought to serve as an elementary mechanism for the establishment of certain forms of explicit memory in the mammalian brain. As is the case with behavioral memory, LTP in the CA1 region has stages: a short-term early potentiation lasting 1 to 3 hours, which is independent of protein synthesis, precedes a later, longer lasting stage (L-LTP), which requires protein synthesis. Inhibitors of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) blocked L-LTP, and analogs of cAMP induced a potentiation that blocked naturally induced L-LTP. The action of the cAMP analog was blocked by inhibitors of protein synthesis. Thus, activation of PKA may be a component of the mechanism that generates L-LTP.     

Comparison of 5-fluorouracil pharmacokinetics in patients receiving continuous 5-fluorouracil infusion and oral uracil plus N1-(2''-tetrahydrofuryl)-5-fluorouracil

In order to examine the relationship between long-term potentiation (LTP) and phosphoinositide (PI) turnover, we evaluated these throughout anesthetized rat brain using carbon-11-labeled diacylglycerol (11C-DAG). High-frequency tetanic stimulation (400 pulses at 400 Hz) to the perforant pathway induced LTP in rat dentate gyrus. In autoradiograms of rat brains, LTP was associated with the occurrence of multiple highly radioactive spots in many regions distant from the stimulated site. Following i.v. administration of an NMDA receptor antagonist prior to stimulation, however, no high-density spots were found. These findings directly demonstrate that potentiation of phosphoinositide-derived signaling was induced during LTP, and the finding of multiple location suggests the occurrence of polysynaptic neurotransmission through neural networks pertaining to learning and memory.     

Synaptic refractory period provides a measure of probability of release in the hippocampus

Despite extensive research, much controversy remains regarding the locus of expression of long-term potentiation (LTP) in area CA1 of the hippocampus, specifically, whether LTP is accompanied by an increase in the probability of release (p(r)) of synaptic vesicles. We have developed a novel method for assaying p(r), which utilizes the synaptic refractory period--a brief 5-6 ms period following release during which the synapse is incapable of transmission (Stevens and Wang, 1995). We show that this assay is sensitive to a battery of manipulations that affect p(r) but find no change following either NMDA receptor-dependent LTP or long-term depression (LTD).