Src activation in the induction of long-term potentiation in CA1 hippocampal neurons

Long-term potentiation (LTP) is an activity-dependent strengthening of synaptic efficacy that is considered to be a model of learning and memory. Protein tyrosine phosphorylation is necessary to induce LTP. Here, induction of LTP in CA1 pyramidal cells of rats was prevented by blocking the tyrosine kinase Src, and Src activity was increased by stimulation producing LTP. Directly activating Src in the postsynaptic neuron enhanced excitatory synaptic responses, occluding LTP. Src-induced enhancement of alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) receptor-mediated synaptic responses required raised intracellular Ca2+ and N-methyl-D-aspartate (NMDA) receptors. Thus, Src activation is necessary and sufficient for inducing LTP and may function by up-regulating NMDA receptors.     

Aging differentially alters forms of long-term potentiation in rat hippocampal area CA1

Long-term potentiation (LTP) of the Schaffer collateral/commissural inputs to CA1 in the hippocampus was shown to consist of N-methyl-D-aspartate receptor (NMDAR) and voltage-dependent calcium channel (VDCC) dependent forms. In this study, the relative contributions of these two forms of LTP in in vitro hippocampal slices from young (2 mo) and old (24 mo) Fischer 344 rats were examined. Excitatory postsynaptic potentials (EPSP) were recorded extracellularly from stratum radiatum before and after a tetanic stimulus consisting of four 200-Hz, 0.5-s trains given 5 s apart. Under control conditions, a compound LTP consisting of both forms was induced and was similar, in both time course and magnitude, in young and old animals. NMDAR-dependent LTP (nmdaLTP), isolated by the application of 10 microM nifedipine (a voltage-dependent calcium channel blocker), was significantly reduced in magnitude in aged animals. The VDCC dependent form (vdccLTP), isolated by the application of 50 microM D,L-2-amino-5-phosphonvalerate (APV), was significantly larger in aged animals. Although both LTP forms reached stable values 40-60 min posttetanus in young animals, in aged animals vdccLTP increased and nmdaLTP decreased during this time. In both young and old animals, the sum of the two isolated LTP forms approximated the magnitude of the compound LTP, and application of APV and nifedipine or genestein (a tyrosine kinase inhibitor) together blocked potentiation. These results suggest that aging causes a shift in synaptic plasticity from NMDAR-dependent mechanisms to VDCC-dependent mechanisms. The data are consistent with previous findings of increased L-type calcium current and decreased NMDAR number in aged CA1 cells and may help explain age-related deficits in learning and memory.     

Early undernutrition impairs hippocampal long-term potentiation in adult rats.

Investigated the effects of early malnutrition on the ability to establish and maintain hippocampal long-term potentiation (LTP), a relatively permanent enhancement of synaptic and cellular responses induced by high-frequency stimulation. Six control male rats and 8 previously undernourished Ss were used in the acute preparation, and 4 controls and 6 previously undernourished Ss in the chronic preparation. Following high-frequency stimulation of hippocampal dentate granule cells, potentiation was difficult to achieve in undernourished Ss. LTP showed a significant decline within 3–6 hrs and was completely absent at 24 hrs. Further trains of stimulation resulted in only small benefits in undernourished Ss. Coupled with previously reported morphological and behavioral deficits, these findings indicate a marked hippocampal dysfunction resulting from early undernutrition and provide a potentially valuable approach for relating nutritionally induced behavioral impairments to brain function. (26 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The projection from hippocampal area CA1 to the subiculum sustains long-term potentiation

Long-term potentiation (LTP) is a popular model of the synaptic plasticity which may be engaged by the biological processes underlying learning and memory. Most available studies of LTP have concentrated on the analysis of LTP occurring in 'early' components of the hippocampal circuit (for example, dentate gyrus and area CA1). We examine here, for the first time, LTP as it occurs in the massive, unidirectional projection from CA1 to the subiculum in vivo. We show that this projection sustains high-frequency stimulus-induced LTP (10 trains of 20 stimuli at 200 Hz; intertrain interval 2 s; LTP 181 +/- 9% at 30 min post-LTP induction). In addition, input-output (I/O) curves show a leftward shift for all stimulation values.     

Effect of low-intensity hippocampal stimulation on spatial versus working memory in rats.

Investigated differing predictions from the spatial mapping hypothesis of hippocampal function proposed by O'Keefe and Nadel (1978) and the working memory hypothesis proposed more recently by Olton and colleagues (Olton, Becker, & Handelmann, 1979). Each of 2 groups of rats was trained to use a different strategy to locate a submerged platform in opaque water. The MAP group used a spatial mapping strategy to reach a platform in a fixed location, whereas the CUE group used a guidance strategy, which involved following a cue that signaled the location of a randomly placed platform. Half of each group was given low-level unilateral electrical stimulation of the dentate gyrus and immediately tested on the water maze task. Results of Exp 1 show that both the MAP and CUE groups were impaired by stimulation. However, there was an inadvertent spatial element involved in the CUE task. When this element was eliminated in Exp 3, the same CUE Ss were unaffected by a 2nd series of stimulation trials, whereas the MAP Ss continued to show impairment. Results strongly support the cognitive mapping hypothesis and provide little support for the working memory hypothesis of hippocampal function. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interaction between paired-pulse facilitation and long-term potentiation in the projection from hippocampal area CA1 to the subiculum

Studies of the interaction between long-term potentiation (LTP) and paired-pulse facilitation (PPF) may throw light on the role of presynaptic factors in LTP. We examine here, for the first time, the nature of PPF in the CA1-subiculum projection. PPF peaks at a 50 ms interstimulus interval (ISI) and is evident at ISIs from 10 to 500 ms. There is no PPF effect at a 1000 ms ISI. PPF decreases in magnitude post-LTP induction across the middle range of ISI values tested (30, 50 and 100 ms). There is a positive correlation between initial PPF values and LTP; this correlation increases as the ISI increases. Initial values and the change in PPF post-LTP are also negatively correlated.     

Effects of prenatal protein malnutrition on hippocampal long-term potentiation in freely moving rats

It has been demonstrated that prenatal protein malnutrition significantly affects hippocampal plasticity, as measured by long-term potentiation, throughout development. This paper focuses on the hippocampal dentate granule cell population response to two separate paradigms of tetanization of the medial perforant pathway in prenatally protein-malnourished and normally nourished adult male rats. The 100-pulse paradigm consisted of the application of ten 25-ms-duration bursts of 400 Hz stimulation with an interburst interval of 10 s. The 1000-pulse paradigm consisted of the application of five 500-ms bursts of 400 Hz stimulation with an interburst interval of 5 s. No between-group differences were obtained for input/output response measures prior to tetanization. No between-group, nor between-paradigm, differences were obtained in the degree of population EPSP slope enhancement. However, in response to both paradigms, prenatally malnourished animals showed significantly less enhancement of the population spike amplitude (PSA) measure than normally nourished animals. Normally nourished animals showed a significantly greater level of PSA enhancement in response to the 100-pulse paradigm than the 1000-pulse paradigm. Prenatally malnourished animals showed no significant differences in the degree of PSA enhancement between the two paradigms. Results indicate that short duration bursts (< or = 25 ms) are more effective in inducing maximal PSA enhancement in normally nourished rats than longer duration stimulus bursts. The apparent inability of prenatally malnourished rats to transfer enhanced cellular activation (population EPSP slope enhancement) into enhanced cellular discharge (PSA enhancement) suggests that a preferential enhancement of GABAergic inhibitory modulation of granule cell excitability may result from the prenatal dietary insult. Such potentiation of inhibitory activity would significantly lower the probability of granule cell population discharge, resulting in the significantly lower level of PSA enhancement obtained from these animals.     

Loss of hippocampal CA1 pyramidal neurons correlates with memory impairment in rats with ischemic or neurotoxin lesions.

Rats were trained for 20 days in a modified T maze to perform an invariant, tactile discrimination and a variable, delayed spatial discrimination, and then were exposed either to 30 min of transient forebrain ischemia or to low- or high-dose ibotenic acid to damage the dorsal hippocampus bilaterally. Only rats exposed to ischemia or high-dose ibotenic acid demonstrated impaired performance during 30 postoperative test days on both aspects of the task (p?p?     

Long-term potentiation and long-term depression in the lateral septum in spatial working and reference memory

We report two experiments conducted on a radial arm maze in the mouse showing that training could either enhance or reduce the efficacy of the fimbria-lateral septal synapses. It is suggested that the direction of change is determined by the kind of situation the animal is faced with (ie trial-dependent, respectively).     

Cognitive enhancers and hippocampal long-term potentiation in vitro

We review our works on the pharmacological modulation of long-term potentiation (LTP) at guinea pig hippocampal mossy fiber-CA3 synapses in vitro. The magnitude of tetanus-induced LTP at the mossy fiber synapse was augmented by perfusion of slices with several cognitive enhancers, such as bifemelane (1 microM). The mossy fiber LTP was enhanced by somatostatin (0.32 microM) and inhibited in somatostatin-depleted slices from cysteamine-treated guinea pigs. An involvement of the 5-HT3 receptor also showed that granisetron (0.1 microM) enhanced the mossy fiber LTP. The above-mentioned enhancements by perfused agents were commonly reversed, at least in part, by muscarinic antagonists. However, the magnitude of mossy fiber LTP was bidirectionally modulated by muscarinic stimulations of slices with physostigmine or carbachol at different concentrations. The enhancing effects of high-concentration carbachol was antagonized by pirenzepine, and in contrast, the inhibition by low-concentration carbachol was antagonized in the presence of AF-DX116. When guinea pigs were preinjected with the cholinotoxin AF64A, the magnitude of LTP was decreased in the slices prepared from AF64A-treated animals. These results suggest that endogenous acetylcholine dominantly plays facilitatory roles through muscarinic M1 receptors in the induction of mossy fiber LTP. The pharmacological characterization of mossy fiber LTP may be of help to the evaluation of cognitive enhancers at a neuronal circuit level.     

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.     

Modified hippocampal long-term potentiation in PKC gamma-mutant mice

Calcium-phospholipid-dependent protein kinase (PKC) has long been suggested to play an important role in modulating synaptic efficacy. We have created a strain of mice that lacks the gamma subtype of PKC to evaluate the significance of this brain-specific PKC isozyme in synaptic plasticity. Mutant mice are viable, develop normally, and have synaptic transmission that is indistinguishable from wild-type mice. Long-term potentiation (LTP), however, is greatly diminished in mutant animals, while two other forms of synaptic plasticity, long-term depression and paired-pulse facilitation, are normal. Surprisingly, when tetanus to evoke LTP was preceded by a low frequency stimulation, mutant animals displayed apparently normal LTP. We propose that PKC gamma is not part of the molecular machinery that produces LTP but is a key regulatory component.     

Galanin inhibits long-term potentiation at Schaffer collateral-CA1 synapses in guinea-pig hippocampal slices

CNSs AND OTHER Master's-prepared nurses are usually expected to lead research utilization (RU) efforts in organizations, but they often feel unprepared to do so. In this article, the need for clinical RU is discussed and ideas for implementation, using an adaptation of the Conduct and Utilization of Research in Nursing model, are described. The RU process is applied to research about once-a-day temperatures in afebrile patients. To assist nurses who are implementing research-based practice, we list studies that were used for the practice change, summarize the research base on the topic, and offer an example of clinical use of practice guidelines.     

Amygdala beta-noradrenergic influence on hippocampal long-term potentiation in vivo

We have previously shown that hippocampal long-term potentiation (LTP), one form of synaptic plasticity that may underlie learning and memory, is attenuated by blocking neuron activity of the basolateral amygdala (BLA). In the present study we investigated the amygdala noradrenergic or cholinergic contribution to hippocampal LTP formation. When propranolol, a beta-adrenoceptor antagonist, was injected into the BLA 10 min before tetanus, the formation of LTP in the perforant path-dentate granule cell synapses was significantly impaired. Scopolamine, a muscarinic cholinergic receptor antagonist, did not affect the formation of LTP. These results suggest that amygdala beta-noradrenergic activity plays a critical role in modulation of hippocampal LTP.     

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)     

Interleukin 1 beta inhibits synaptic strength and long-term potentiation in the rat CA1 hippocampus

Cytokines such as interleukin-1 beta (IL-1 beta) are released in the nervous system following inflammation or infection. Recently, IL-1 beta was shown to enhance synaptic inhibitory mechanisms. We therefore investigated the effect of IL-1 beta superfusion on long-term potentiation (LTP), the cellular model of memory and learning, evoked in the CA1 region by tetanic stimulation of the stratum radiatum in the rat hippocampal slice. IL-1 beta (150 pM-1.5 nM) superfused 10 min before tetanic stimulation significantly reduced LTP of the slope of the population excitatory postsynaptic potential (pEPSP) and the population spike (PS) amplitude in CA1 in a concentration-dependent manner. IL-1 beta (1.5 nM) applied for 10 min 1 h before tetanus significantly inhibited LTP of the PS amplitude and pEPSP slope and reduced pEPSP and PS values before tetanus as well, although the PS returned to control values before tetanus. Heat-inactivated IL-1 beta had no effect on pre-tetanus pEPSP or PS values or the induction of LTP. These data demonstrate that IL-1 beta modulates synaptic potentials and reduces LTP. These findings have important implications for the role of IL-1 beta in neuronal disorders following infection, perhaps best exemplified by HIV-1-associated dementia.     

Two forms of long-term potentiation in area CA1 activate different signal transduction cascades

1. The effects of protein kinase inhibitors on N-methyl-D-aspartate (NMDA)-receptor-mediated, voltage-dependent calcium channel (VDCC)-mediated, and 100-Hz long-term potentiation (LTP) were studied in area CA1 of rat hippocampal slices. 2. A 25-Hz tetanus induced a quickly developing potentiation that was blocked by the NMDA antagonist D,L-2-amino-5-phosphonovaleric acid (APV) and was not affected by the L-type VDCC inhibitor nifedipine, suggesting that it was mediated by NMDA receptors (NMDA-LTP). 3. Application of a 200-Hz tetanus in APV induced a slowly developing NMDA-receptor-independent potentiation that was blocked by nifedipine and thus named VDCC-LTP. NMDA- and VDCC-LTP reached comparable magnitudes despite their different induction parameters and developmental kinetics. 4. Bath perfusion of the broad-spectrum serine/threonine kinase inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) blocked NMDA-LTP but not VDCC-LTP, whereas the tyrosine kinase inhibitors genistein and lavendustin A blocked VDCC-LTP but not NMDA-LTP. These results suggest a differential involvement of H-7-sensitive serine/threonine kinases and tyrosine kinases in the two forms of LTP. 5. Tetanization of 200 Hz in control media resulted in a compound potentiation twice as large as NMDA- or VDCC-LTP, implying that the two forms of LTP did not facilitate or reduce each other's expression. The often-used 100-Hz tetanus (1 s twice) induced a potentiation that was comparable in size with the 200-Hz compound LTP. Nifedipine, genistein, and lavendustin A reduced the 100-Hz LTP by approximately 50%, suggesting that this LTP is also a compound potentiation consisting of NMDA- and VDCC-mediated components and their corresponding signal transduction pathways.     

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.