Impairment of long-term potentiation in rat hippocampus following chronic ethanol treatment

The effect of chronic ethanol treatment on long-term potentiation (LTP), a possible substrate for memory, was studied in rats using the in vitro hippocampal slice preparation. Rats were provided ad libitum access to an ethanol-containing or control liquid diet. One group of animals received the diet for a total period of 9 months before testing, while a second group received the diet for 7 months and was allowed a 2 month ethanol-free period before testing. LTP was induced in the CA1 region by orthodromic stimulation of the stratum radiatum with 4 stimulus trains of 200 pulses each at 25, 50, 100 and 200 Hz separated by 10 min intervals. The number of slices with potentiation greater than 15% was significantly smaller in the ethanol-fed animals both before and following the 2 month withdrawal period. However, the average percent increase in the amplitude of the population spike was significantly decreased in the ethanol-fed animals when tested before withdrawal but no significant difference was detected following the 2 month withdrawal period, suggesting some recovery. The possible mechanisms mediating the chronic ethanol-induced depression of LTP are discussed.     

Hippocampal long-term potentiation increases mitochondrial calcium pump activity in rat

⁴⁵Ca²⁺ pump activity was measured in hippocampal homogenates after the induction of long-term potentiation (LTP) of perforant path-dentate gyrus synapses in vivo. The mitochondrial poison, sodium azide, was used to separate mitochondrial from non-mitochondrial⁴⁵Ca²⁺ uptake. High-frequency stimulation of the perforant path input produced a selectively increased mitochondrial uptake of calcium. This increased pump activity may permit granule cells to more effectively buffer higher intracellular calcium levels associated with LTP.     

Long-term potentiation in the hippocampal slice: Possible involvement of pyruvate dehydrogenase

Tetanic stimulation of fibers in the hippocampal slice preparation produces long-term potentiation (LTP) and also decreases the in vitro incorporation of phosphate into the alpha subunit of pyruvate dehydrogenase (αPDH)¹². This paper describes 6 experiments that were undertaken to replicate this observation. Hippocampal slices were incubated in a specially designed chamber and stimulated with a tungsten wire electrode in the stratum radiatum for 1 s at 100 Hz. Two minutes after the tetanus, the stimulated slices were removed alternately with control (not tetanized) slices and each group was pooled for subcellular fractionation and labeling of the fractions with [³²P]ATP. Proteins were separated by electrophoresis and relative³²P contents of 41K and 50K protein bands were studied. Tetanic stimulation of the stratum radiatum did not affect subsequent phosphorylation of a 50K M_r protein that has been reported to be altered by perforant path activation². Stimulation also had no effect on pyruvate dehydrogenase enzyme activity or on the ratio of active (dephosphorylated) to inactive enzyme. In most cases tetanic stimulation produced no significant change in the in vitro phosphorylation of this enzyme. Only under one set of conditions, labeling with 250 μM [γ-³²P] ATP for 10 s, was a decrease in the in vivo labeling of αPDH shown to be statistically significant. These findings suggest that LTP is not necessarily accompanied by an initial change in PDH phosphorylation level or activity but may be associated with a decrease in the kinase activity directed toward this protein.     

Calcium uptake and retention during long-term potentiation of neuronal activity in the rat hippocampal slice preparation

Alterations in⁴⁵Ca uptake and retention as well as total intracellular calcium content were measured in hippocampal ‘in vitro’ slice preparations following the induction of long-term potentiation (LTP) in CA1 pyramidal neurones. The results indicate that tetanic stimulation of the Schaffer-commissural input produces a significant increase in the uptake and retention of calcium which parallels LTP of the CA1 population spike response.     

Calcium channel blockers and Alzheimer’s disease

Alzheimer’s disease is characterized by two pathological hallmarks: amyloid plaques and neurofi-brillary tangles. In addition, calcium homeostasis is disrupted in the course of human aging. Recent research shows that dense plaques can cause functional alteration of calcium signals in mice with Alzheimer’s disease. Calcium channel blockers are effective therapeutics for treating Alzheimer’s disease. This review provides an overview of the current research of calcium channel blockers in-volved in Alzheimer’s disease therapy.     

Postsynaptic firing during repetitive stimulation is required for long-term potentiation in hippocampus

Long-term potentiation (LTP) in the hippocampus is a long lasting enhancement of the postsynaptic evoked response following high frequency, repetitive stimulation of afferents. The extracellularly recorded action potential (population spike) can be reversibly blocked, without affecting the extracellular recorded excitatory postsynaptic potential, by focal application of γ-aminobutyric acid, tetrodotoxin, or pentobarbital, to the CA1 pyramidal cells of the hippocampal slice. When the population spike is blocked during repetitive stimulation, LTP does not occur. It appears that postsynaptic firing of action potentials during repetitive stimulation is necessary to produce LTP.     

Hypothesis regarding the cellular mechanisms responsible for long-term synaptic potentiation in the hippocampus

A possible cellular mechanism accounting for the long-term potentiation (LTP) of synaptic transmission in the hippocampus is presented. Our multiple-stage hypothesis postulates that repetitive stimulaion causes an increase of intracellular calcium in the target dendritic regions which results in the activation of a membrane-associated protease which in turn exposes additional glutamate receptors.     

Cerebrovascular and neurological perspectives on adrenoceptor and calcium channel modulating pharmacotherapies

Adrenoceptor and calcium channel modulating medications are widely used in clinical practice for acute neurological and systemic conditions. It is generally assumed that the cerebrovascular effects of these drugs mirror that of their systemic effects – and this is reflected in how these medications are currently used in clinical practice. However, recent research suggests that there are distinct cerebrovascular-specific effects of these medications that are related to the unique characteristics of the cerebrovascular anatomy including the regional heterogeneity in density and distribution of adrenoceptor subtypes and calcium channels along the cerebrovasculature. In this review, we critically evaluate existing basic science and clinical research to discuss known and putative interactions between adrenoceptor and calcium channel modulating pharmacotherapies, the neurovascular unit, and cerebrovascular anatomy. In doing so, we provide a rationale for selecting vasoactive medications based on lesion location and lay a foundation for future investigations that will define neuroprotective paradigms of adrenoceptor and calcium channel modulating therapies to improve neurological outcomes in acute neurological and systemic disorders.     

Dendritic calcium mechanisms and long-term potentiation in cortical inhibitory interneurons

Calcium (Ca(2+) ) is a major second messenger in the regulation of different forms of synaptic and intrinsic plasticity. Tightly organized in space and time, postsynaptic Ca(2+) transients trigger the activation of many distinct Ca(2+) signaling cascades, providing a means for a highly specific signal transduction and plasticity induction. High-resolution two-photon microscopy combined with highly sensitive synthetic Ca(2+) indicators in brain slices allowed for the quantification and analysis of postsynaptic Ca(2+) dynamics in great detail. Much of our current knowledge about postsynaptic Ca(2+) mechanisms is derived from studying Ca(2+) transients in the dendrites and spines of pyramidal neurons. However, postsynaptic Ca(2+) dynamics differ considerably among different cell types. In particular, distinct rules of postsynaptic Ca(2+) signaling and, accordingly, of Ca(2+) -dependent plasticity operate in GABAergic interneurons. Here, I review recent progress in understanding the complex organization of postsynaptic Ca(2+) signaling and its relevance to several forms of long-term potentiation at excitatory synapses in cortical GABAergic interneurons.     

The role of monosialoganglioside GM1 in the synaptic plasticity: in vitro study on rat hippocampal slices

Rat hippocampal slices were incubated with neuraminidase from Vibrio Cholerae. This enzyme liberates sialic acid from polysialogangliosides converting them into monosialoganglioside GM1. Thus, the tissue is enriched in GM1 content. Another set of slices was incubated with GM1 itself. Both treatments increased the magnitude of potentiation of synaptic response recorded from pyramidal cell layer following high frequency stimulation of Schaffer collateral-commissural fibers. It is concluded that enrichment of synaptic membranes in GM1 enhances the ability of these nerve endings to be potentiated.     

Involvement of NMDA receptors and voltage-dependent calcium channels on augmentation of long-term potentiation in hippocampal CA1 area of morphine dependent rats

The involvement of NMDA receptors and voltage-dependent calcium channels on augmentation of long-term potentiation (LTP) was investigated at the Schaffer collateral–CA1 pyramidal cell synapses in hippocampal slices of morphine dependent rats, using primed-bursts tetanic stimulation. The amplitude of population spike was measured as an index of increase in postsynaptic excitability. d,l-AP5 and nifedipine were used as NMDA receptor antagonist and voltage-dependent calcium channel blocker, respectively. The amount of LTP of orthodromic population spike amplitude was higher in slices from dependent rats. Perfusion of slices from control or dependent rats with ACSF containing either d,l-AP5 (25 μM) or nifedipine (10 μM) and delivering tetanic stimulation, showed that d,l-AP5 completely blocked LTP of OPS in slices from both control and dependent rats, while nifedipine attenuated the amount of LTP of OPS in dependent slices and had no effect on control ones. The results suggest that the enhanced LTP of OPS in the CA1 area of hippocampal slices from morphine dependent rats is primarily induced by the NMDA receptors activity and the voltage-dependent calcium channels may also be partially involved in the phenomenon.     

Inhibition of rabbit platelet phosphodiesterase activity and aggregation by calcium channel blockers

Rabbit platelet cyclic AMP phosphodiesterase is inhibited by the three calcium channel blockers nifedipine, diltiazem, and verapamil with IC50's of 100 microM, 100 microM and 420 microM, respectively. Also, platelet aggregation induced by 4 microM ADP is inhibited by those compounds. Verapamil is the most potent aggregation inhibitor with an IC50 of 260 microM while diltiazem and nifedipine have IC50's of 630 microM and 840 microM, respectively. All three compounds display a maximum inhibition of 80-85%. Diltiazem and PGD2 potentiate the antiaggregatory activity of each other in that the inhibitions occurring in the presence of the combination of the two (at varying concentrations) exceed the calculated sums of the inhibitions produced by each alone. On the other hand, the antiaggregatory activities of verapamil or nifedipine, are additive with that of PGD2 in that no significant differences exist between the observed inhibitions produced by the combinations and the calculated summed values of the individual inhibitions. Our data suggest, therefore, that in addition to lowering intracellular calcium ions, which are required for platelet aggregation, the three calcium channel blockers inhibit the breakdown of cyclic AMP thereby promoting antiaggregation.     

硫胺素缺乏早期对成年小鼠认知功能及海马突触长时程增强的影响

Objective To investigate the changes of cognitive function and the hippocampal long-term potentiation (LTP) in adult mice in early stage of thiamine deficiency (TD). Methods Twenty-four adult mice were randomized into normal control group and experimental group, and in the latter group, the mice were given thiamine-depleted diet for 9 days to induce TD. The learning and memory abilities of the mice were tested with Y-maze test, and the LTP in the hippocampal CA1 and CA3 regions was measured electrophysiologically. Results Feeding on thiamine-depleted diet for 9 days significantly increased the total training trials in the learning task as compared with those of the normal control mice (23±0.86 vs 13.50±1.28, P<0.05), but the memory ability of the two groups remained comparable (P>0.05). By field potential recording in the hippocampal CA1 and CA3 regions, theta burst stimulation induced similarly robust LTP in the control and experimental groups (P>0.05). Conclusion The learning ability of adult mice is impaired in early stage of TD, the mechanism of which does not obviously involve hippocampai synaptic plasticity.     

Perforant pathway-evoked long-term potentiation of CA1 neurons in the hippocampal slice preparation

Previously, we have presented electrophysiological evidence reaffirming the existence of a controversial hippocampal pathway. These fibers are part of the perforant pathway and terminate directly on the CA1 cells. We now report that, in the hippocampal slice preparation, tetanic stimulation of the perforant pathway produces long-term potentiation (LTP) of CA1 cell responses. LTP of population spikes varied from 150% to 500%. The results were of interest because these axons synapse at distal sites on the apical dendrite. This location is usually thought to be a difficult site to evoke action potentials.     

L‐type calcium channel blocker ameliorates diabetic encephalopathy by modulating dysregulated calcium homeostasis

Diabetic encephalopathy is a complication of diabetes characterized by impaired cognitive functions. The objective of the present study was to examine the beneficial effect of the calcium channel blocker, nimodipine, on diabetes‐induced cognitive deficits and altered calcium homeostasis in the cerebral cortex. Diabetes was induced in mice by intraperitoneal injection of streptozotocin (40 mg/kg body wt) for 5 days. Nimodipine (10 mg/kg body weight) was administered intraperitoneally to the animals every 48 hr for 8 weeks. A significant impairment in spatial learning and memory was observed in diabetic animals, which was reversed by nimodipine treatment. Diabetic animals showed increased CaV1.2 mRNA and protein expression, which might be responsible for enhanced synaptosomal calcium uptake. Nimodipine treatment was found to lower CaV1.2 mRNA, protein expression, and calcium uptake. Mitochondrial Ca²⁺ uptake was reduced in diabetic brains, which was reversed with nimodipine treatment. Plasma membrane and sarcoplasmic reticulum Ca²⁺‐ATPase activity was found to be significantly decreased in diabetic animals, whereas nimodipine supplementation restored the activity of both Ca²⁺‐ATPases nearly to control values. Nimodipine treatment was shown to normalize intracellular free Ca²⁺ levels in diabetic animals. Nimodipine was shown to attenuate increased calpain activity measured in terms of hydrolysis of fluorogenic substrate and αII‐spectrin degradation. Nimodipine supplementation also reduced reactive oxygen species production and lipid peroxidation in diabetic animals. The data suggests that L‐type calcium channel blocker is beneficial in preventing cognitive deficits associated with diabetic encephalopathy through modulation of dysregulated calcium homeostasis. © 2014 Wiley Periodicals, Inc.     

Age differences in a circadian influence on hippocamapl LTP

Data from several experiments on long-term potentiation (LTP) in the rat hippocampus were examined for circadian influence. Incidence and magnitude of LTP produced in both area CA1 and area dentata were analyzed, and a reciprocal light/dark difference was found in the two areas, with pyramidal cells of area CA1 showing more LTP during the light period and granule cells of area dentata showing more LTP during the dark period. In addition, results from experiments on developing animals, suggested that the circadian influence on LTP in either area was not present before postnatal day 20. All of these experiments were from hippocampal slice preparations; therefore, it is important to note that circadian influences on hippocampal LTP are preserved in the in vitro environment where tonic extrahippocampal input has presumably been removed.     

Thermal effects on long-term potentiation in the hamster hippocampus

Extracellular CA1 pyramidal cell activity was measured at different temperatures in hippocampal slices from the Syrian hamster (Mesocricetus auratus), a hibernator. Control records taken before and after tetanic stimulation of Schaffer collateral/commissural pathways were compared to determine if long-term potentiation (LTP) was established. LTP (an enhancement of the population spike amplitude or population synaptic response following tetanus) was elicited in slices at temperatures above 22 °C, but not in slices at temperatures of 20 °C. When LTP was established at temperatures above 24 °C, however, lowering the temperature to 20 °C did not abolish the LTP. Furthermore, when a tetanus was delivered at 20 °C and the bath temperature was then raised above 22 °C, LTP was established. These results for step changes in temperature suggest that the sequence of cellular mechanisms leading to LTP is activated, but then arrested in slices maintained at a constant temperature of 20 °C. Assuming this type of activity in the slice parallels in vivo hippocampal activity, it follows that the ability to elicit LTP in CA1 hippocampal pyramidal cells is lost when the core temperature of an animal entering hibernation falls to 20 °C.     

Large long-lasting potentiation in the dentate gyrus in vitro during blockade of inhibition

The sequence of regeneration following intracranial optic nerve crush has been studied using electrophysiological visual mapping in the frog Hyla moorei. Compared to our earlier series with extracranial crush, the time course was slower and the intermediate projections more disorganized. It is suggested that the apparent discrepancy between the early patterns of regeneration in Xenopus and Rana compared to Hyla, fish and newt, is not due to species differences but to the location of the lesion site.     

Influence of epidermal growth factor on long-term potentiation in the hippocampal slice

Rat hippocampal slices were perfused with epidermal growth factor (EGF) at a concentration of 10(-8) M. EGF is a well known mitogen which exhibits neurotrophic action on neurons of the CNS. During extra- and intracellular recordings in the pyramidal cell body layer of the CA1-region no influence of EGF on evoked potentials was seen if single-pulse or paired-pulse stimulation was used. Furthermore EGF has no influence on the resting membrane potential of the cells investigated. However after tetanic stimulation a significant increase in the magnitude of long-term potentiation was observed. Therefore it is concluded, that EGF might be involved in modulation of neuronal plasticity.     

Inhibitory effect of calcium channel blockers on proliferation of human glioma cells in vitro

The effects of 2 specific calcium channel blockers, verapamil and nimodipine, on the proliferation of human glioma tumour cells were investigated in vitro. Tumour tissues for primary cell cultures were obtained bioptically from 3 patients with the histopathological diagnosis of glioblastoma. The [3H]-thymidine incorporation into glioma tumour cells DNA was used as a sensitive index of the cell proliferation. It was found that verapamil (10(-4)-10(-5) M) and nimodipine (10(-4)-10(-6) M) significantly inhibited the [3H]-thymidine uptake in a dose-related manner. The inhibitory effect of both calcium channel antagonists was reversed by simultaneous addition of calcium chloride (5 x 10(-3) M). These results indicate that verapamil and nimodipine may exert an antiproliferative effect on glioma cells growth acting through a blockade of specific voltage-dependent calcium channels.