Spatial memory processing during hippocampal long-term potentiation in rats.

It was investigated in rats whether hippocampal long-term potentiation (LTP) influences working and/or reference memory processing in the radial maze. After preliminary training to an intermediate level of performance, experimental subjects received a series of high-frequency trains of electrical pulses applied to the right perforant path. Two control groups were adopted in order to control for possible effects of stimulation plus operation, and operation alone, respectively. Twenty-four hours after the experimental treatment, animals were administered one trial of radial maze training. This sequence of hippocampal stimulation and radial maze training was replicated 15 times. After a retention interval of 2 months, one radial maze trial was presented on each of 3 consecutive days. The analysis of field potential data showed that periodic LTP stimulation produced a state of hippocampal LTP confined to the initial portion of the acquisition phase. Evaluation of radial maze data revealed a marginal improvement of working memory performance in the experimental group during the rising phase of hippocampal LTP.     

Site and time dependent effects of acute stress on hippocampal long-term potentiation in freely behaving rats

The phasic effects of stress-induced elevations of corticosterone on long-term potentiation (LTP) were investigated in the hippocampus of awake, freely behaving rats. Field potential recordings were performed in the dentate gyrus with stimulation of the medial perforant pathway or the CA1 with stimulation of the commissural/associational pathway, on the contralateral hemisphere. LTP was induced either shortly (1 h) after acute stress or 4 h later. Animals were either adrenalectomized or adrenally intact. A subgroup of animals were injected with a low dose of dexamethasone 4 h prior to the stressor, in order to suppress the corticosterone response to restraint stress, and they were tested for LTP in the dentate gyrus 4 h after the stressor. In the dentate gyrus, stress had no effect on LTP induction at 1 h post-stress; however, it produced a significant suppression at the 4 h interval. As expected, adrenalectomized rats did not show stress-suppression of LTP, but showed a lower level of LTP with or without stress. Supporting a role of stress-induced glucocorticoid secretion in LTP suppression, dexamethasone treatment of adrenally intact animals blocked the acute stress suppression of LTP in the dentate gyrus. In the CA1 field, restraint stress did not significantly affect LTP induction at either the 1- or 4-h post-stress intervals. Similarly, stress by itself, did not significantly affect neuronal excitability in either the dentate gyrus or CA1 hippocampal field at either the 1- or 4-h post-stress interval. The present results suggest that stress affects synaptic plasticity differently at the two hippocampal subfields and that the effects are time-dependent and involve the stress-induced surge of glucocorticoids.     

Effects of experimental hypercapnia on hippocampal long-term potentiation in anesthetized rats

The effects of hypercapnia, which has been reported to impair consciousness, on the long-term potentiation of the population spike in the CA1 pyramidal cell of the hippocampus in anesthetized rats were studied. Experimental hypercapnemia was induced by inspired 13% CO₂ with 21% O₂. Arterial blood gas analysis after 80 min inspired 13% CO₂ showed pH 7.08±0.05, PCO₂=104.09±12.86 mmHg, PO₂=90.71±18.89 mmHg, BE −4.64±2.97 (mean±SD, n=18). Inspired 13% CO₂ reduced the amplitude of the population spike to 50% of the baseline. After delivery of tetanic stimulation (400 Hz, five bursts of eight pulses, inter-burst interval 1 s) population spike height was enhanced to pre-tetanic levels. Withdrawal of inspired CO₂ unmasked an increase in population spike amplitude. These findings suggest that acute retention of carbon dioxide, which is designated as pure hypercapnemia without hypoxemia, may suppress hippocampal synaptic transmission but not its plasticity.     

Effects of experimental hypercapnia on hippocampal long-term potentiation in anesthetized rats

Neuronal voltage-dependent P/Q Ca2+ channels are genetically abnormal in many cases of familial hemiplegic migraine and possibly associated with the more common forms of migraine with and without aura. Besides the brain, these channels are found in motor nerve endings where they control stimulation-induced acetylcholine release. Using single fiber EMG recordings we were able to demonstrate subclinical abnormalities of neuromuscular transmission in a subgroup of patients suffering from migraine with aura. This could be related to genetic abnormalities of P/Q Ca2+ channels in certain patients suffering from migraine with aura, which needs to be explored by proper genetic analyses.     

Increased Ca-uptake of presynaptic terminals during long-term potentiation in hippocampal slices

Summary A combined electrophysiological and neurochemical study was performed on the CA1 area of hippocampal slices in an attempt to identify changes in presynaptic nerve terminal function in long-term potentiation (LTP). After controlled induction of LTP in CA1, the activated region was subjected to subcellular fractionation followed by ⁴⁵Ca²⁺ uptake determinations. Synaptosomes prepared from slices in which LTP has been induced showed a faster risetime and a higher level of saturation for K⁺-induced Ca-uptake than those derived from unstimulated and stimulated control slices. These findings point to a participation of presynaptic terminals in long-term potentiation.     

Amyloid beta prevents activation of calcium/calmodulin-dependent protein kinase II and AMPA receptor phosphorylation during hippocampal long-term potentiation

Accumulation of amyloid beta-peptides (Abeta) in the brain has been linked with memory loss in Alzheimer's disease and its animal models. However, the synaptic mechanism by which Abeta causes memory deficits remains unclear. We previously showed that acute application of Abeta inhibited long-term potentiation (LTP) in the hippocampal perforant path via activation of calcineurin, a Ca2+ -dependent protein phosphatase. This study examined whether Abeta could also inhibit Ca2+/calmodulin dependent protein kinase II (CaMKII), further disrupting the dynamic balance between protein kinase and phosphatase during synaptic plasticity. Immunoblot analysis was conducted to measure autophosphorylation of CaMKII at Thr286 and phosphorylation of the GluR1 subunit of AMPA receptors in single rat hippocampal slices. A high-frequency tetanus applied to the perforant path significantly increased CaMKII autophosphorylation and subsequent phosphorylation of GluR1 at Ser831, a CaMKII-dependent site, in the dentate area. Acute application of Abeta1-42 inhibited dentate LTP and associated phosphorylation processes, but was without effect on phosphorylation of GluR1 at Ser845, a protein kinase A-dependent site. These results suggest that activity-dependent CaMKII autophosphorylation and AMPA receptor phosphorylation are essential for dentate LTP. Disruption of such mechanisms could directly contribute to Abeta-induced deficits in hippocampal synaptic plasticity and memory.     

Spatial working memory is independent of hippocampal CA1 long-term potentiation in rats

This study investigated the relationship between spatial working memory and hippocampal long-term potentiation (LTP) using the allocentric place discrimination task (APDT) in rats, in which the selection accuracy is a good index for spatial working memory. Either the selective M1 muscarinic receptor antagonist pirenzepine (50 microg) or the choline uptake inhibitor hemicholinium-3 (5 microg) impaired APDT selection accuracy, but neither affected the induction of LTP in the hippocampal CA1 region in anesthetized rats. In contrast, the selective N-methyl-D-aspartate receptor antagonist D-amino-5-phosphonopentanoate (200 nmol) did not impair APDT selection accuracy but completely blocked hippocampal CA1 LTP. These results suggest that spatial working memory is independent of hippocampal CA1 LTP and that the central cholinergic system is involved in spatial working memory, but not through the modulation of hippocampal CAI LTP.     

外源性硫化氢对海洛因依赖大鼠海马长时程增强的影响

目的:观察外源性H2S供体NaHS对海洛因依赖大鼠学习记忆能力及海马LTP的影响。方法:SD大鼠随机分成3组:正常对照组、heroin组、heroin+NaHS组。先通过跳台实验检测大鼠学习记忆能力,然后记录高频刺激(HFS)前后在体海马CA1区群体峰电位(PS)变化,诱导长时程增强(LTP)的产生,最后通过Nissl染色观察海马神经元的损伤情况。结果:与对照组比较,heroin组和heroin+NaHS组学习记忆成绩均降低(P<0.05),PS幅值变化率减小(P<0.01),且形态学观察可见海马神经元损伤;与heroin组比较,heroin+NaHS组学习记忆成绩提高(P<0.05),PS幅值变化率增大(P<0.01),海马神经元损伤较轻。结论:(1)海洛因依赖导致大鼠海马神经元损伤,抑制海马CA1区LTP的产生,从而降低正常学习记忆能力;(2)外源性H2S可减轻海洛因依赖对大鼠海马神经元的损伤,易化海马CA1区LTP的产生,改善海洛因依赖导致的正常学习记忆能力的降低。     

葡萄糖浓度降低对幼龄鼠及成年鼠海马长时程增强的影响

目的:观察葡萄糖浓度降低对幼龄鼠15-16日龄及成年鼠56-63日龄海马CA1区长时程增强(LTP)诱发的影响。方法:采用脑片灌流及电生理学技术,以场兴奋性突触后电位的初始斜率(S-EPSP)为观测指标。结果:当将灌流液中葡萄糖浓度降为3或1.5mmol/L时,S-EPSP显著减小。在葡萄糖浓度为3或1.5mmol/L的介质中,以高频刺激(HFS)作用于成年鼠脑片仅出现短时程增强反应;但在葡萄糖浓度为3mmol/L的介质中,HFS仍可在幼龄鼠脑片上诱导出LTP。结论:低糖可使突触的传递活动减弱;在突触可塑性方面,幼龄鼠对低糖的耐受性要强于成年鼠。     

Enhancement of extracellular protein concentrations during long-term potentiation in the rat hippocampal slice.

The possibility that the enhancement of extracellular protein concentrations during long-term potentiation is related to the maintenance of long-term potentiation was examined in area CA1 of rat hippocampal slices. First, we found that during the 3 h after induction, long-term potentiation maintenance was correlated with a persistent enhancement of extracellular protein concentrations. Second, when the protein synthesis inhibitor cycloheximide was applied 10-15 min before long-term potentiation induction, the drug blocked both the maintenance of long-term potentiation and the elevation of extracellular protein concentrations. These results suggest that the elevation of extracellular protein concentrations requires new protein synthesis. The results further indicate that the newly synthesized proteins may play a role in the maintenance of long-term potentiation.     

Inhibitory effects of calcitonin gene-related peptide on long-term potentiation induced in hippocampal slices of rats

It is well known that hippocampus plays important roles in learning and memory. Both calcitonin gene-related peptide (CGRP) and CGRP receptors are found in hippocampus. In the present study we explored the influence of CGRP on long term potentiation (LTP) in hippocampal Schaffer collateral-CA1. Our results demonstrated that CGRP inhibited the LTP induced by high frequency stimulation (HFS) in hippocampal CA1 neurons in rat brain slices. The inhibitory effect was blocked by CGRP receptor-1 antagonist CGRP 8-37. The results indicate that both CGRP and CGRP receptor 1 are involved in the modulation process of LTP in hippocampus of rats.     

Inhibitory effects of calcitonin gene-related peptide on long-term potentiation induced in hippocampal slices of rats

This study was designed to determine whether a 5-HT_2C receptor antagonist could induce a conditioned place preference indicative of reward and/or abuse potential. Here, we present the first evidence that a selective 5-HT_2C receptor antagonist, 6-chloro-5-ethoxy-N-(pyridin-2-yl)indoline-1-carboxamide hydrochloride (CEPC), can potentiate a low dose (0.5 mg/kg) amphetamine-induced positive conditioned place preference (CPP). CEPC did not produce any CPP given alone at doses of either 2.0 or 4.0 mg/kg, whereas low dose amphetamine alone produced only a slight, but statistically nonsignificant, place preference. These studies suggest that 5-HT_2C receptor antagonists can indirectly potentiate the rewarding effects of amphetamine, and perhaps other psychostimulants. If the results can be translated to man, putative 5-HT_2C receptor antagonist treatments for anxiety or depression may enhance or potentiate the rewarding effects of drugs of abuse such as amphetamine, which release dopamine.     

Subcortical deafferentation impairs behavioral reinforcement of long-term potentiation in the dentate gyrus of freely moving rats

Long-term potentiation is a form of neural functional plasticity which has been related with memory formation and recovery of function after brain injury. Previous studies have shown that a transient early-long-term potentiation can be prolonged by direct stimulation of distinct brain areas, or behavioral stimuli with a high motivational content. The basolateral amygdala and other subcortical structures, like the medial septum and the locus coeruleus, are involved in mediating the reinforcing effect. We have previously shown that the lesion of the fimbria-fornix--the main entrance of subcortical afferents to the hippocampus--abolishes the reinforcing basolateral amygdala-effects on long-term potentiation in the dentate gyrus in vivo. It remains to be investigated, however, if such subcortical afferents may also be important for behavioral reinforcement of long-term potentiation. Young-adult (8 weeks) Sprague-Dawley male rats were fimbria-fornix-transected under anesthesia, and electrodes were implanted at the dentate gyrus and the perforant path. One week after surgery the freely moving animals were studied. Fimbria-fornix-lesion reduced the ability of the animals to develop long-term potentiation when a short pulse duration was used for tetanization (0.1 ms per half-wave of a biphasic stimulus), whereas increasing the pulse duration to 0.2 ms per half-wave during tetanization resulted in a transient early-long-term potentiation lasting about 4 h in the lesioned animals, comparable to that obtained in non-lesioned or sham-operated control rats. In water-deprived (24 h) control animals, i.e. in non-lesioned and sham-operated rats, early-long-term potentiation could be behaviorally reinforced by drinking 15 min after tetanization. However, in fimbria-fornix-lesioned animals long-term potentiation-reinforcement by drinking was not detected. This result indicates that the effect of behavioral-motivational stimuli to reinforce long-term potentiation is mediated by subcortical, heterosynaptic afferents.     

Modulation of hippocampal long-term potentiation by slow increases in ethanol concentration

To determine how acute ethanol intoxication may alter memory processing, we examined the effects of stepwise increases in ethanol on long-term potentiation (LTP) in rat hippocampal slices. LTP was inhibited by acute administration of 60 mM ethanol, but was readily induced if ethanol was increased gradually to 60 mM over 75 min. Administration of 2-amino-5 phosphonovalerate (APV), an N-methyl-D-aspartate receptor (NMDAR) antagonist, during the stepwise increase in ethanol inhibited LTP, suggesting involvement of NMDARs in the development of tolerance. However, APV and nifedipine, an inhibitor of L-type calcium channels, failed to inhibit LTP when administered following the slow increase in ethanol. Ethanol-tolerant LTP was inhibited by thapsigargin, suggesting a major role for intracellular calcium release in this form of plasticity. The unique properties of ethanol-tolerant LTP suggest that memories formed during binge drinking are not acquired by standard synaptic mechanisms and that acute tolerance may involve the induction of novel mechanisms to maintain function.     

Effects of ventral hippocampal long-term potentiation and depression on the gamma-band local field potential in anesthetized rats

We examined the effect of long-term potentiation or depression (LTP or LTD) on the local field potential, focusing on the gamma-band (40–100 Hz) power, in the ventral hippocampus CA1 of anesthetized rats. LTP and LTD induction in the CA3–CA1 pathway increased the CA1 spontaneous gamma-band power by around 40 and 80–100 Hz, respectively, while neither changed the evoked levels significantly. These results suggest that the ventral CA1 local field potential can maintain bidirectional plasticity in the steady state for the long term. Given the involvement of synaptic plasticity in learning and memory, the gamma-band power change associated with LTP/LTD may relate to ventral hippocampal functions. The LTP increased the spontaneous power at around 40 Hz of the gamma-band frequency in the ventral CA1, and the LTD did the same at 80–100 Hz. The biphasic increase may distribute the subsequent input appropriately to regulate the relevant synaptic history in the ventral CA1 and anatomically related structures in vivo.     

Effects of potentiated antibodies to brain specific protein S100 on the dynamics of long-term potentiation in hippocampal slices

Native monoclonal antibodies to neurospecific S100 protein completely prevented the development of long-term potentiation (LTP) in rat hippocampal slices. Potentiated antiserum prepared by multiple dilutions according to homeopathic procedure (1:10¹²) did not affect LTP, but abolished the effect of native antiserum when applied 20 min prior to it. Neither nonimmune rabbit serum at the same dilution nor homeopathic solvent modified the development of LTP in hippocampal slices. Translated fromByulleten' Eksperimental'noi Biologii I Meditsiny, Vol. 127, No. 3, p. 317–321, March 1999     

Agonistic behavior during stress prevents the development of learned helplessness in rats

Male Wistar rats were subjected to unavoidable electrical pain stimulation either in individual cages or in pairs. During the procedure, rats stressed in pairs fought. After 48 h, rats were tested in a shuttle box for the ability to develop active avoidance responses. The proportion of escape and avoidance responses was significantly lower in rats stressed individually as compared with intact animals and animals stressed in pairs. Plasma corticosterone was assayed one day later, at rest and aftere dexamethasone administration. There were no significant differences in resting corticosterone levels between groups of animals. Administration of dexamethasone significantly reduced the plasma corticosterone level in intact rats and in animals stressed in pairs, but not in rats stressed individually. Thus, agonistic behavior during unavoidable stress prevents the development of pathological changes in adaptive behavior and the endocrine system. I. P. Pavlov Institute of Physiology, Russian Academy of Sciences, 6 Makarov Bank, 199034 St. Petersburg, Russia. Department of Higher Nervous Activity, St. Petersburg State University, 7/9 Universitetskaya Bank, 199034 St. Petersburg, Russia. Translated from Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 82, No. 12, pp. 6–11, December, 1996.     

Mice deficient in endothelial nitric oxide synthase exhibit a selective deficit in hippocampal long-term potentiation

Long-term potentiation, a persistent increase in synaptic efficacy, may require a retrograde signal originating in the postsynaptic cell that induces an increase in presynaptic neurotransmitter release. We have constructed a mouse homozygous for a targeted null mutation in the endothelial isoform of nitric oxide synthase and report that long-term potentiation in the CA1 region of these mice is entirely absent under weak stimulation conditions. Application of a membrane-permeant guanosine-3′,5′-cyclic monophosphate analogue during tetanus fails to compensate for this deficit, suggesting that nitric oxide produced by endothelial nitric oxide synthase may affect long-term potentiation through a cascade that does not include guanylyl cyclase. We also report that strong tetanic stimulation can induce robust long-term potentiation in these mice which is not blocked by pharmacological inhibitors of nitric oxide synthase. Furthermore, mice lacking endothelial nitric oxide synthase show no shift in the frequency–response curve for the induction of long-term potentiation. Basal synaptic transmission, paired-pulse facilitation and the electrical properties of CA1 cells in these mice were similar to controls.

These results support a selective role for endothelial nitric oxide synthase in long-term potentiation, but also demonstrate that nitric oxide synthase is not involved in this process under all conditions.