Pharmacology of long-term potentiation

The exotic or non-indigenous species model for deliberately introduced genetically engineered organisms (GEOs) has often been misunderstood or misrepresented. Yet proper comparisons of of ecologically competent GEOs to the patterns of adaptation of introduced species have been highly useful among scientists in attempting to determine how to apply biological theory to specific GEO risk issues, and in attempting to define the probabilities and scale of ecological risks with GEOs. In truth, the model predicts that most projects may be environmentally safe, but a significant minority may be very risky. The model includes a history of institutional follies that also should remind workers of the danger of oversimplifying biological issues, and warn against repeating the sorts of professional misjudgements that have too often been made in introducing organisms to new settings. We once expected that the non-indigenous species model would be refined by more analysis of species eruptions, ecological genetics, and the biology of select GEOs themselves, as outlined. But there has been political resistance to the effective regulation of GEOs, and a bureaucratic tendency to focus research agendas on narrow data collection. Thus there has been too little promotion by responsible agencies of studies to provide the broad conceptual base for truly science-based regulation. In its presently unrefined state, the non-indigenous species comparison would overestimate the risks of GEOs if it were (mis)applied to genetically disrupted, ecologically crippled GEOs, but in some cases of wild-type organisms with novel engineered traits, it could greatly underestimate the risks. Further analysis is urgently needed.     

Contrast effects in escape conditioning of rats.

In Exp I 39 male Holtzman albino rats ran for 20 trials from an alley where they received .2-, .4-, or .8-ma shocks to a goal box where there was no shock. All Ss were then shifted to .4 ma in the alley for 20 trials. Results show that rapid adjustment of running speeds occurred with shifts in amount of escapable shock. More importantly, however, positive and negative contrast occurred. In Exp I an experimental group (n = 10) received .2 ma on half of the trials and .4 ma on the other half, and 2 control groups (n = 10) received either .4 or .2 ma on all trials. Results show that the experimental group escaped faster on .4-ma trials than the .4-ma control group (positive contrast) and escaped more slowly on .2-ma trials than the .2-ma control (negative contrast). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

In vitro long-term potentiation of electrotonic responses of goldfish mauthner cells is accompanied by ultrastructural changes at afferent mixed synapses

The potentiated afferent mixed synapses of the Mauthner cells of fry and adult goldfish in stumps of the medulla oblongata incubated long-term in vitro were studied by electrophysiological and electron microscopic methods. It was shown that brief high-frequency stimulation of posterior branches of the eighth nerve induced a long-term potentiation of electrotonic transmission at large and small mixed club endings. It was about 135% upon subthreshold stimulation and about 200% upon suprathreshold stimulation. The ultrastructural analysis of ultrathin sections of potentiated mixed synaptic endings revealed an increase in the dimensions of desmosome-like contacts which was proportional to the degree of potentiation, about 135% or 200%, depending on the type of stimulation. The dimensions of gap junctions remained unchanged. The dimensions of active zones at potentiated synapses were reduced two-fold as compared with their unpotentiated counterparts, irrespective of the type of stimulation. Considering that desmosome-like contacts consist predominantly of F-actin, a molecule which possesses electroconductivity, it can be assumed that this cytoskeletal protein is involved in the process of potentiation. The increase in the synapse electrical conductivity can be mediated either directly, by shunting the synaptic junction with polymer actin filaments in the region of desmosome-like contacts, or indirectly, via the interaction of actin with gap junction connections situated nearby.     

Quantitative two-process analysis of avoidance conditioning in goldfish.

The shuttlebox performance of goldfish was studied under standardized conditions in a variety of problems: with or without an avoidance contingency, a CS-termination contingency, and an escape contingency. The effects of CS-only, unconditioned stimulus/stimuli (UCS)-only, and explicitly unpaired training were also examined. All data could be simulated quantitatively with a version of O. H. Mowrer's (1947) 2-process theory expressed in 2 learning equations (one classical, the other instrumental) and a performance equation. The good fit suggests that the theory is worth developing further with new experiments designed to challenge it. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Parallel augmentation of hippocampal long-term potentiation, theta rhythm, and contextual fear conditioning in water-deprived rats.

The influence of water deprivation on hippocampal long-term potentiation (LTP), theta rhythm, and contextual fear conditioning in 56 adult male rats was examined. In Exp 1, hippocampal EEG activity and perforant path LTP were assessed in pentobarbital-anesthetized rats. Water deprivation did not affect baseline cell excitability or low-frequency synaptic transmission in the dentate gyrus, but it increased the magnitude of perforant path LTP and elevated the proportion of theta rhythm in the EEG. In Exp 2, rats were classically conditioned to fear a novel context through the use of aversive footshocks. Water deprivation facilitated the rate of contextual fear conditioning but did not alter the asymptote of learning. Exp 3 demonstrated that the facilitation of contextual fear conditioning was not due to a change in unconditional shock sensitivity. These results suggest that water deprivation exerts an influence on contextual fear conditioning by modulating hippocampal LTP and theta rhythm and that these processes serve to encode contextual information during learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Importance of polysynaptic inputs and horizontal connectivity in the generation of tetanus-induced long-term potentiation in the rat auditory cortex

Supragranular pyramidal neurons in the adult rat auditory cortex (AC) show marked long-term potentiation (LTP) of population spikes after tetanic white matter stimulation (TS). For determination of whether this marked LTP is specific to AC, LTP in rat AC slices was compared with LTP in slices of the visual cortex (VC). The amplitude of TS-induced LTP in AC was twice that in VC. LTP of EPSPs was also studied with perforated patch or whole-cell recording. Although the amplitude of TS-induced LTP of EPSPs in AC was larger that in VC, no cortical difference was found in LTP elicited by low-frequency stimulation paired with current injection. Neocortical LTP is dependent on the activation of NMDA receptors, and induction of LTP requires postsynaptic depolarization for removal of Mg2+ blockade of NMDA receptors. The postsynaptic depolarization elicited by TS in supragranular pyramidal neurons in AC was significantly larger than that in VC. Cutting of supragranular horizontal connections resulted in a decrease in the depolarization amplitude in AC but an increase in the depolarization amplitude in VC. The cortical difference in TS-induced LTP was diminished in the slices in which horizontal connections in supragranular layers were cut. The estimated density of horizontal axon collaterals of supragranular pyramidal neurons in AC was approximately twice that in VC. These results strongly suggest that the marked polysynaptic and postsynaptic depolarization during TS and the resulting marked LTP in AC are attributed to well developed horizontal axon collaterals of supragranular pyramidal neurons in AC.     

Two forms of hippocampal long-term depression, the counterpart of long-term potentiation

In the hippocampus there are two distinct forms of long-term depression (LTD) of excitatory synaptic transmission. In the CA1 region, prolonged low-frequency stimulation induces LTD by activating postsynaptic NMDA receptors, which causes a moderate rise in Ca2+ concentrations. In mossy fiber synapses of the CA3 region, similar low-frequency stimulation also gives rise to LTD. However, this form of LTD (mossy fiber LTD) does not require activation of NMDA receptors, but is mediated by activation of presynaptic metabotropic glutamate receptors. Induction of mossy fiber LTD is not dependent on postsynaptic depolarization or activation of postsynaptic ionotropic glutamate receptors, thus it is likely to be mediated by purely presynaptic mechanisms. This conclusion is confirmed by the analysis of mutant mice lacking presynaptic mGluR2, in which mossy fiber LTD is almost absent. Since long-term potentiation at mossy fiber synapses is also induced presynaptically, the synaptic efficacy may be regulated through common mechanisms bidirectionally, which may contribute to neural information processing in the hippocampus.     

Pavlovian analysis of avoidance conditioning in the goldfish (Carassius auratus).

Conducted 2 experiments in which 144 and 54 goldfish, respectively, were trained in a shuttlebox with light as CS and brief shock as UCS. Performance was measured in terms of "initial response" to the CS (at least 1 crossing of the hurdle on any trial) and-where the CS was not terminated by the initial response-in terms of "multiple response" to the CS (more than 1 crossing on any trial). The level of initial responding was as high in classically conditioned Ss (shocked on every trial) as in avoidance Ss, whether or not the CS was terminated by response, but lower in control Ss, yoked with the avoidance Ss, and lower also in punished Ss (shocked only if they responded). Multiple responding was negligible in avoidance Ss, but common in classically conditioned and in punished Ss. Results can be accounted for in purely Pavlovian terms, no reference to instrumental learning being required. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Increased susceptibility to induction of long-term depression and long-term potentiation reversal during aging

Homosynaptic long-term depression (LTD) and reversal of long-term potentiation (LTP) were examined extracellularly at CA3-CA1 synapses in stratum radiatum of slices from adult (6-9 months) and aged (20-24 months) Fischer 344 rats. Prolonged low-frequency stimulation (LFS) (900 pulses/1 Hz) of the Schaffer collaterals depressed the initial slope of the excitatory postsynaptic potential (EPSP) in aged but not adult rats. LTD at aged synapses was pathway-specific, persistent, and sensitive to the NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid (AP5). Adult slices exhibited AP5-sensitive LTD in high [Ca2+] medium, whereas LTD in aged slices was blocked by high [Mg2+], suggesting that differences in Ca2+ regulation may underlie susceptibility to LTD. Despite age-related differences in LTD induction, no age difference in LTP magnitude was revealed. Additionally, LFS delivered 60 min after LTP induction resulted in similar LTP reversal for both age groups. Susceptibility differences to LTP reversal were indicated after multiple short-duration LFS bursts (30 pulses/1 Hz), with each burst separated by 10 min. Aged synapses exhibited significant reversal after a single burst and complete reversal after three LFS episodes. In adult slices, LTP reversal appeared after the fourth burst, and at no time was LTP depressed to initial baseline levels. This study provides the first characterization of homosynaptic LTD/LTP reversal in the aged animal and demonstrates that one form of plasticity, depression attributable to LFS, is increased during aging.     

Two different forms of long-term potentiation in the hippocampus

Several forms of long-term potentiation (LTP), a putative cellular mechanism for memory storage, have been described in the hippocampus. In this review, I discuss the mechanisms of induction and expression of LTP at the Schaffer collateral synapses and at the mossy fiber pathway. The early biochemical steps responsible for LTP at these two pathways are well understood. However, future studies should transcend the study of signal transduction systems and focus on the identification of the synaptic proteins that experience activity-dependent modifications, ultimate effectors of the plastic changes.     

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.     

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.     

Involvement of calmodulin-dependent protein kinases-I and -IV in long-term potentiation

BACKGROUND: The Hemopump (DLP/Medtronic) has been in clinical use for about 7 years. There is still no adequate way of determining actual output from the three available pump systems in the clinical situation. If the pump is completely stopped during weaning from the device, there is a possibility of back-leakage through the pump, endangering the patient from regurgitation into the left ventricle. It can also make it more difficult to judge the recovery of heart function because of a volume load of the left ventricle. The aim of this study was to evaluate in a standardized, experimental in vitro model the output from three different-sized Hemopump catheters at various pressure levels and to quantify the back-flow through the pumps. METHODS: The Hemopump models were tested in an in vitro study regarding total outflow at various speeds at three pressure levels. The back-flow through the pumps was also measured with the pumps at a complete stop. RESULTS: The outflow from the Hemopumps ranged from 0.4 to 4.5 L/min, depending on which pump and speed were used. Variations in total output, depending on speed and various pressure settings, could be up to 0.4 L/min. Back-flow through the pump into the left ventricle may be as great as 1.6 L/min. CONCLUSIONS: The flow outputs from the different Hemopump models were reproducible over time and were closely related to the resistance of the model. The Hemopump, if not running, can induce substantial regurgitation through the pump into the left ventricle.     

Dose-response study of dehydroepiandrosterone sulfate on dentate gyrus long-term potentiation

To examine the role of tenascin (TN) in vivo, we have produced mice in which the TN gene is inactivated. In behavioral studies, TN-knockout mice showed abnormal behavior such as hyperlocomotion and poor swimming ability. Biochemical analysis revealed that serotonin (5-HT) and dopamine (DA) transmission was decreased in the cerebral cortex, the hippocampus, or the striatum of TN-knockout mouse brain. The intraperitoneal administration of the DA receptor agonist, LY171555 (0.5 mg/kg, BW), inhibited the hyperlocomotion, and swimming behavior was transiently improved by the treatment with the 5-HT receptor agonist, 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride. These findings suggest that TN may play an important role in neurotransmissions related to behavior.     

Protein kinase C inhibitors block generation of anoxia-induced long-term potentiation

The aim of this study was to study the possible intracellular mechanisms underlying the anoxia-induced long-term potentiation (anoxic LTP) in the CA1 neurons of rat hippocampal slices using extra- and intracellular recording techniques. Superfusion of the hippocampal slices with the protein kinase C (PKC) inhibitors NPC-15437 (20 microM) or H-7 (20 microM) specifically prevented the induction of anoxic LTP. Moreover, the anoxic LTP was completely abolished in neurons intracellularly recorded with the selective PKC inhibitor PKCI 19-36 (50 microM). The specific cAMP-dependent protein kinase (PKA) inhibitor Rp-cyclic adenosine 3',5'-monophosphate (Rp-cAMPS, 25 microM) had no effect on the anoxic LTP. It is concluded that induction of anoxic LTP requires the activation of postsynaptic PKC.     

Involvement of dendritic adhesion molecule telencephalin in hippocampal long-term potentiation

Telencephalin (TLCN) is a cell adhesion molecule belonging to the immunoglobulin superfamily whose expression is restricted to neurons within the most highly developed brain segment, telencephalon. Immunoelectronmicroscopic study revealed that in the hippocampal CA1 region, TLCN was localized at the surface membrane of postsynaptic spines of pyramidal cell dendrites but not at that of axonal terminals. Blocking of TLCN function using anti-TLCN antibody or recombinant soluble TLCN protein caused a striking suppression of the long-term potentiation (LTP) at the Schaffer collateral-CA1 synapses. The suppression was observed even when the blocking was initiated immediately after the tetanic stimuli. These observations suggest a role for TLCN-mediated cell-cell interactions as a key step in the development of LTP.     

Synapse specificity of long-term potentiation breaks down at short distances

Long-term potentiation (LTP), the long-lasting increase in synaptic transmission, has been proposed to be a cellular mechanism essential for learning and memory, neuronal development, and circuit reorganization. In the original theoretical and experimental work it was assumed that only synapses that had experienced concurrent pre- and postsynaptic activity are subject to synaptic modification. It has since been shown, however, that LTP is also expressed in synapses on neighbouring neurons that have not undergone the induction procedure. Yet, it is still believed that this spread of LTP is limited to adjacent postsynaptic cells, and does not occur for synapses on neighbouring input fibres. However, for technical reasons, tests for 'input specificity' were always done for synapses relatively far apart. Here we have used a new local superfusion technique, which allowed us to assess the synaptic specificity of LTP with a spatial resolution of approximately 30 microm. Our results indicate that there is no input specificity at a distance of less than 70 microm. Synapses in close proximity to a site of potentiation are also potentiated regardless of their own history of activation, whereas synapses far away show no potentiation.     

Protected-site phosphorylation of protein kinase C in hippocampal long-term potentiation

One important aspect of synaptic plasticity is that transient stimulation of neuronal cell surface receptors can lead to long-lasting biochemical and physiological effects in neurons. In long-term potentiation (LTP), generation of autonomously active protein kinase C (PKC) is one biochemical effect persisting beyond the NMDA receptor activation that triggers plasticity. We previously observed that the expression of early LTP is associated with a phosphatase-reversible alteration in PKC immunoreactivity, suggesting that autophosphorylation of PKC might be elevated in LTP. In the present studies we tested the hypothesis that PKC phosphorylation is persistently increased in the early maintenance of LTP. We generated an antiserum that selectively recognizes the alpha and betaII isoforms of PKC autophosphorylated in the C-terminal domain. Using western blotting with this antiserum we observed an NMDA receptor-mediated increase in phosphorylation of PKC 1 h after LTP was induced. How is the increased phosphorylation maintained in the cell in the face of ongoing phosphatase activity? We observed that dephosphorylation of PKC in vitro requires the presence of cofactors normally serving to activate PKC, i.e., Ca2+, phosphatidylserine, and diacylglycerol. Based on these observations and computer modeling of the three-dimensional structure of the PKC catalytic core, we propose a "protected site" model of PKC autophosphorylation, whereby the conformation of PKC regulates accessibility of the phosphates to phosphatase. Although we have proposed the protected site model based on our studies of PKC phosphorylation in LTP, phosphorylation of protected sites might be a general biochemical mechanism for the generation of stable, long-lasting physiologic changes.     

Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation

A novel property of hippocampal LTP, 'variable persistence', has recently been described that is, we argue, relevant to the role of LTP in information storage. Specifically, new results indicate that a particular pattern of synaptic activation can give rise, either to a relatively short-lasting LTP, or to a longer-lasting LTP as a function of the history of activation of the neuron. This has led to the idea that the induction of LTP is associated with the setting of a'synaptic tag' at activated synapses, whose role is to sequester plasticity-related proteins that then serve to stabilize temporary synaptic changes and so extend their persistence. In this article, we outline the synaptic tag hypothesis, compare predictions it makes with those of other theories about the persistence of LTP, and speculate about the cellular identity of the tag. In addition, we outline the requirement for aminergic activation to induce late LTP and consider the functional implications of the synaptic tag hypothesis with respect to long-term memory.