Potassium-induced long-term potentiation in rat hippocampal slices

We observed that a transient increase in extracellular potassium concentration (50 mM for 40 s) was sufficient to induce long-term potentiation (LTP) of synaptic transmission in area CA1 of the hippocampal slice. Potassium-induced potentiation of the Schaffer collateral/commissural synapses demonstrated several features characteristic of tetanus-induced LTP: (1) population excitatory post-synaptic potential (EPSP) amplitudes were enhanced to a similar magnitude (on average 70% above baseline) which (2) lasted for more than 20 min; (3) induction was blocked by bath application of the specific N-methyl-d-aspartate (NMDA) receptor antagonistd-2-amino-5-phosphonovalerate (d-APV), and (4) was attenuated by reduction of the concentration of calcium in the extracellular medium. Induction of either potassium-induced LTP or tetanus-induced LTP occluded the subsequent expression of the other. Finally, exposure to high potassium in the absence of electrical stimulation was sufficient to induce LTP. Taken together, these data indicate that brief depolarizing stimuli other than tetanus can induce LTP. Because potassium-induced LTP is not restricted to the subset of afferents examined electrophysiologically, such a method could facilitate analyses of the biochemical events underlying both the induction and expression of LTP.     

GABA能去抑制水平的变化对海马CAl突触长时程增强的影响

目的 研究改变中间神经元GABA能抑制水平对海马CA1区突触长时程增强(LTP)的影响.同时获得不同浓度Bicuculline阻断GABAA受体介导抑制以及影响海马CA1区突触可塑性详细信息. 方法 应用膜片钳全细胞记录技术记录成年小鼠海马脑片上自发的微小的抑制性突触后电位(mIPSC)和诱发的前馈抑制性突触后电流(IPSC),使用细胞外电生理方法 记录刺激Schaffer侧枝诱发的CA1区辐射层场的兴奋性突触后电位(fEPSP],测量不同浓度Bicuculline对mIPSC、IPSC和fEPSP的作用,以及它们对小鼠海马脑片CA1区突触LTP的影响. 结果 10μmol/L、20μmol/L Bicuculline可以减弱mIPSC和IPSC抑制性突触电流,且20 μmol/L Bicuculline作用更明显;20μmol/L Bicuculline可以明显提高fEPSP的斜率,而5 μmol/L和10 μmol/LBicuculline没有明显作用;5 μmol/L、10 μmol/L、20μmol/L和50μmol/L Bicuculline组100赫兹强直刺激诱发后的fEPSP平均斜率均值都大于对照组,但仅10 μmol/L、20 μmol/L两组相比,差异有统计学意义(P<0.05). 结论 Bicuculline可以减弱GABAA受体介导的抑制以及增加场的fEPSP斜率,并且Bicuculline阻断GABA能抑制到一个关键水平才可以增强海马CA1区突触的LTP.     

Developmental changes in long-term potentiation in CA1 of rat hippocampal slices

Long-term potentiation (LTP) was examined in the CA1 region of rat hippocampal slices at postnatal day 9 (P9), P15, P30, P60, P90, P120, and P300. A single 100 Hz × 1 sec tetanus failed to induce LTP in P9 slices, while similar degrees of LTP were observed at P15, P30, and P60. At P30, changes in population spike (PS) amplitudes were accurately predicted by changes in dendritic excitatory postsynaptic potentials (EPSPs). However, at P15, the predicted increase in PS calculated from corresponding changes in dendritic EPSPs was significantly less than the observed increase, suggesting that EPSP-PS dissociation (ES-dissociation) plays a substantial role in LTP at P15. Additionally, the corresponding changes in somatic EPSP height measured in the CA1 cell layer did not predict the E-S dissociation at P15, suggesting that the E-S dissociation arises largely from changes in the excitability of the soma. Using a single 100 Hz × 1 sec tetanus, LTP proved difficult to induce in slices from rats ≥ P90, with slices showing initial enhancement that faded over 60 min of monitoring. © 1995 Wiley-Liss, Inc.     

Effect of intermittent hypoxia on long-term potentiation in rat hippocampal slices

Intermittent hypoxia (IH) during sleep has been shown to induce apoptosis in a time-dependent manner and spatial learning deficits in adult rats. Recently, we have demonstrated that IH induced significant decreases in Ser-133-phosphorylated cAMP-response element-binding protein (pCREB) without changes in total CREB. The expression of cleaved caspase 3 in the hippocampal CA1, a marker of apoptosis, peaked at 3 days of IH and returned to normoxic values at 14 days of IH. In addition, biphasic changes in spatial task learning were correlated with the CREB phosphorylation time course. In the present study, the rat hippocampal slice preparation was used to evaluate the ability to induce and maintain a CA1 population spike long-term potentiation (PS-LTP) in room air (RA)-maintained and IH-exposed rats. A significant decrease in the ability to sustain PS-LTP for 15 min in slices prepared from IH-exposed rats for either 3 days (34% of total) or 7 days (51% of total) as compared to slices prepared from RA-maintained rats (76% of total) was observed. These results suggest that the diminishment in the ability of neuronal tissue to express and sustain PS-LTP is correlated with previously reported biphasic changes in CREB phosphorylation and programmed cell death.     

Impaired expression of long-term potentiation in hippocampal slices 4 and 48 h following mild fluid-percussion brain injury in vivo

The effect of fluid percussion brain injury on hippocampal long-term potentiation (LTP) was investigated in hippocampal slices in vitro. Mild to moderate (1.7–2.1 atm) lateral fluid percussion head injury or sham operation was produced in rats 4 or 48 h prior to harvesting brain slices from the ipsilateral hippocampus. Field excitatory post-synaptic potentials (fEPSPs) were recorded in stratum radiatum of hippocampal subfield CA1 in response to electrical stimulation of the Schaffer collaterals. The initial slope of fEPSPs was used to investigate changes in synaptic strength prior to and following 100 or 200 Hz (1 s) tetanic stimulation. TBI significantly inhibited expression of LTP in hippocampal slices in vitro. Post-tetanus fEPSP slopes increased more than 100% in hippocampal slices from sham-operated animals but less than 50% in slices from rats following TBI. The data suggest that changes in functional synaptic plasticity in the hippocampus may contribute to cognitive disorders associated with TBI (traumatic brain injury). The data also indicate that TBI-induced effects on hippocampal LTP are robust and may be investigated in the hippocampal slice preparation in vitro.     

Fucose and fucosyllactose enhance in-vitro hippocampal long-term potentiation

Bath application of -fucose and -fucosyllactose ( F1 increases the potentiation of the population spike amplitude (POP-spike) and the field excitatory postsynaptic potential (fEPSP) after tetanization of the Schaffer collaterals of the rat hippocampus. The ineffective isomers -fucose and 3-fucosyllactose (3-F1) have no such effect. Since not only the maintenance of long-term potentiation LTP is influenced but also its induction is drastically improved, an effect of the sugars via the formation of glycoproteins but also via different actions on induction mechanisms is discussed.     

Enduring suppression of hippocampal long-term potentiation following traumatic brain injury in rat

This study investigated changes in synaptic responses (population spike and population EPSP) of CA1 pyramidal cells of the rat hippocampus to stimulation of the Schaffer collateral/commissural pathways 2-3 h after traumatic brain injury (TBI). TBI was induced by a fluid percussion pulse delivered to the parietal epidural space resulting in loss of righting responses for 4.90-8.98 min. Prior to tetanic stimulation, changes observed after the injury included: (1) decreases in population spikes threshold but not EPSP thresholds; (2) decreases in maximal amplitude of population spikes as well as EPSPs. TBI also suppressed long-term potentiation (LTP), as evidenced by reductions in post-tetanic increases in population spikes as well as EPSPs. Since LTP may reflect processes involved in memory formation, the observed suppression of LTP may be an electrophysiological correlate of enduring memory deficits previously demonstrated in the same injury model.     

Alterations in calmodulin content in fractions of rat hippocampal slices during tetanic- and calcium-induced long-term potentiation

The content of cytosolic and membrane-bound calmodulin was radioimmunologically determined in fractions of rat hippocampal slices 5 min to 7 hours after long-term potentiation (LTP) had been induced by tetanization or exposure of slices to 4 mM Ca++. In light of concepts presuming multistage dynamics in LTP development as reflecting different cellular mechanisms, similar patterns of calmodulin alterations were observed with both models: The alterations in calmodulin content occurred during the early phase(s) of LTP development and continued for two and one hours during tetanic- and calcium-induced LTP, respectively. Thus, 5-30 min after LTP elicitation, membrane-bound calmodulin increased while cytosolic calmodulin diminished and, inversely, 30 min later an increase in cytosolic and decrease in membrane-bound calmodulin were observed. Consequently, the present results indicate that calmodulin was involved in the early phases(s) of LTP development in terms of a two-step translocation sequence. Hence, calmodulin translocation within both intracellular compartments may reflect the involvement of Ca++-calmodulin-dependent intraneuronal metabolic processes which might induce and/or temporarily maintain neuronal functional changes occurring immediately after repeated or intense stimulation of synaptic functions.     

Ethanol differentially modulates GABAA receptor-mediated chloride currents in hippocampal,cortical, and septal neurons in rat brain slices

Previous electrophysiological studies have reported conflicting results concerning the effects of ethanol on γ-aminobutyric acid-A (GABA_A) receptor-mediated responses in the brain. To examine the variables that might explain these inconsistencies, the present study was designed to determine whether ethanol modulation of synaptically evoked GABA responses is brain region dependent, to identify factors that might regulate ethanol sensitivity, and to investigate the mechanism(s) underlying ethanol modulation of GABA responses. Whole-cell voltage clamp methods were used to examine the effects of ethanol on synaptically evoked GABA_A inhibitory postsynaptic currents (IPSCs) recorded from neurons in hippocampus, cerebral cortex, and intermediate lateral and medial septum from rat brain slice preparations. Bicuculline-sensitive IPSCs elicited by local stimulation were pharmacologically isolated by pretreatment with the glutamate specific antagonists, DL-(?)-2-amino-5-phosphonovaleric acid (APV) and 6,7-dinitroquinoxaline-2,3-dione (DNQX). Superfused ethanol (80 mM) potentiated evoked GABA_A IPSCs in cortical neurons and in intermediate lateral and medial septal neurons but not in CA1 hippocampal neurons. However, the mechanism by which ethanol enhanced GABA_A IPSC amplitudes differed between brain regions. In cortex, ethanol induced a hyperpolarizing shift in the GABA_A IPSC reversal potential (E_IPSC) without modifying the underlying GABA_A receptor-mediated conductance (G_IPSC). In contrast, ethanol enhanced GABA_A IPSC amplitudes in lateral and medial septal neurons by increasing the G_IPSC without modifying the E_IPSC These results suggest that ethanol differentially modulates responses to endogenous GABA released during synaptic activation and that important differences between various brain regions may reflect multiple mechanisms of ethanol action. © 1994 Wiley-Liss, Inc.     

Pharmacological treatment dose-relatedly improves learning and hippocampal long-term potentiation

In the CA1 region of hippocampal slices prepared from guinea-pigs, which had been orally treated with sabeluzole, long-term potentiation was significantly enhanced in those slices obtained from animals given 2.5 or 10.0 mg/kg. In an active avoidance task oral treatment of guinea-pigs with 2.5 or 10.0 mg/kg of sabeluzole significantly increased learning. The dose of 0.63 mg/kg was inactive in both paradigms. These results provide new evidence supporting the involvement of LTP in learning.     

Chronic exposure to environmental levels of lead impairs in vivo induction of long-term potentiation in rat hippocampal dentate

This study examined the effects of chronic developmental lead (Pb) exposure in rats on hippocampal long-term potentiation (LTP). Male offspring were exposed to 0.2% Pb acetate continuously from birth until testing at 85–105 days. Excitatory postsynaptic potential (EPSP) and population spike amplitudes were measured in the dentate hilar region in response to stimulation applied to the lateral perforant path. LTP was induced in control animals with an average maximal EPSP potentiation of 41%, which was significantly greater than the increase in EPSP amplitudes (2%) in exposed animals after tetanizing stimulation. Current-voltage curves in controls demonstrated significant increases in EPSPs and population spikes after application of pulse trains to induce LTP, while exposed rats exhibited no discernible change in responses. These findings suggest that induction or development of LTP in the dentate hilar region in vivo is impaired by chronic developmental exposure to environmentally relevant levels of Pb.     

Time-dependent changes in rat hippocampal synapsin I mRNA expression during long-term potentiation

We studied the time-dependent changes in synapsin I mRNA levels after hippocampal long-term potentiation (LTP) in rats in vivo. Following LTP induction by stimulating the perforant path, synapsin I mRNA expression in the granule cell layer of the dentate gyrus ipsilateral to stimulation increased significantly in a time-dependent manner. From 2 to 8 h after stimulation, the synapsin I mRNA levels in the ipsilateral dentate gyrus were significantly higher than those of controls subjected to a sham procedure. The synapsin I mRNA level (157.4±7.1% of the control level, mean±SEM) was at a maximum 8 h after stimulation. The synapsin I mRNA level of animals that received only test pulses did not increase significantly, compared with the control level. These results suggest that the increased level of synapsin I mRNA is related to persistent enhancement of synaptic activity within the neural networks in which dentate granule cells participate in LTP.     

Effects of lamotrigine on field potentials and long-term potentiation in guinea pig hippocampal slices

PURPOSE: To investigate the effects of lamotrigine (LTG), a new anticonvulsant, on neuronal excitability, synaptic transmission, and long-term potentiation (LTP) in guinea pig hippocampal slices. METHODS: Electrically evoked field excitatory postsynaptic potentials (fEPSPs) and population spikes (PSs) were investigated in the CA1 region of the hippocampus. RESULTS: The concentration-response curves showed different actions of LTG in concentrations near therapeutic plasma levels (10 microM) on fEPSPs and PSs. The initial slopes of fEPSPs were not affected, whereas the amplitudes of PSs were significantly decreased. Higher concentrations of LTG decreased both fEPSP slopes and PS amplitudes; however, the effects on PSs were much stronger. Also, there were no differences in fEPSP slopes or PS amplitudes compared with controls when LTP was induced in the presence of LTG (10 microM). CONCLUSIONS: Our data are in contrast to previous findings that suggest LTG acts primarily on presynaptic sites by blocking the release of excitatory amino acids. Further, LTP was not affected by LTG.     

Changes of K+ -Cl- cotransporter 2 (KCC2) and circuit activity in propofol-induced impairment of long-term potentiation in rat hippocampal slices

Enhancing inhibition via gamma-aminobutyric acid type A (GABA_A) receptors contributes to anesthetic-induced impairment of long-term potentiation (LTP) of excitatory synaptic transmission, which may account for general anesthesia-associated memory impairment (amnesia). The neuron-specific K⁺–Cl⁻ cotransporter 2 (KCC2) is necessary for fast synaptic inhibition via maintaining the low intracellular chloride concentration required for the hyperpolarizing actions of GABA via GABA_A receptors. To explore a possible role of KCC2-dependent inhibition in anesthetic-induced impairment of LTP, we used field excitatory postsynaptic potentials (fEPSP) recording and immunoblotting to study the effect of propofol on LTP maintenance and KCC2 expression in CA1 region of rat hippocampal slices. We found that propofol (30 μM) not only impaired LTP expression but also prevented LTP-accompanied downregulation of KCC2 without affecting the basal transmission of glutamatergic synapses. Moreover, the recurrent inhibition in hippocampal slices was enhanced by propofol. These propofol-induced effects were completely abolished by picrotoxin, a specific GABA_A receptor-chloride channel blocker. Thus, enhancement of GABAergic inhibition and suppression of neuronal excitability may account for the sustained expression of KCC2 and the impairment of LTP by propofol. Together, this study supports a novel role for KCC2 in LTP expression and gives hints to a molecular mechanism, by which anesthetics might cause impairment of LTP.     

Estrogen modulates sexually dimorphic contextual fear conditioning and hippocampal long-term potentiation (LTP) in rats

The present study examined the role of ovarian steroids in contextual fear conditioning and hippocampal synaptic plasticity in female rats. In experiment 1, adult female rats were ovariectomized and submitted to contextual fear conditioning, a procedure in which rats received unsignaled footshock in a novel observation chamber; freezing behavior served as the measure of conditional fear. Ovariectomized female rats froze at levels comparable to male rats, both of which froze significantly more than sham-operated female rats. In experiment 2, estrogen replacement in ovariectomized female rats reduced fear conditioning to a level comparable to that of sham-operated females in experiment 1. In experiment 3, the influence of estrogen on the induction of long-term potentiation (LTP) at perforant path-dentate granule cell synapses in ovariectomized female rats was examined. Estrogen decreased both population spike LTP and EPSP-spike potentiation at perforant path synapses. Taken together, these experiments indicate that ovarian steroids regulate both sexually dimorphic behavior and hippocampal plasticity in a fear-conditioning paradigm.     

Interleukin-6 inhibits long-term potentiation in rat hippocampal slices

The effects of recombinant human interleukin-6 (rhIL-6) on long-term potentiation (LTP) induced in the Schaffer collateral/commissural-CA1 pathway were examined using rat hippocampal slices. Field excitatory postsynaptic potential was recorded in the stratum radiatum of the CA1 region. Ten-min applications of rhIL-6 (50–2000 U/ml), started 5 min before the tetanus, significantly inhibited the induction of LTP, and in high doses of rhIL-6 also inhibited short-term potentiation (over 200 U/ml) and post-tetanic potentiation (over 500 U/ml). The effects of rhIL-6 (500 U/ml) were completely abolished by the preincubation of the slices with monoclonal anti-IL-6 receptor antibody (16 μg/ml) for 2 h. Heat-inactivated rhIL-6 had no effect on the synaptic potentiation. RhIL-6 affected neither the previously established LTP nor the basal synaptic transmission. These findings indicated that rhIL-6 modulated synaptic potentiation through the IL-6 receptor-mediated process in the hippocampus, probably by affecting post- and presynaptic sites in the CA1 region. The possible mechanisms of the IL-6-induced suppression of the synaptic potentiation were discussed.     

Prenatal morphine exposure enhances seizure susceptibility but suppresses long-term potentiation in the limbic system of adult male rats

The present study examined the effects of prenatal morphine exposure on NMDA-dependent seizure susceptibility in the entorhinal cortex (EC), and on activity-dependent synaptic plasticity at Schaffer collateral and perforant path synapses in the hippocampus. During perfusion with Mg(2+)-free ACSF, an enhancement of epileptiform discharges was found in the EC of slices from prenatally morphine-exposed male rats. A submaximal tetanic stimulation (2x50 Hz/1 s) in control slices elicited LTP at the Schaffer collateral-CA1 synapses, but neither LTP nor LTD was evoked at the perforant path-DG synapses. In slices from prenatally morphine-exposed adult male rats, long-term potentiation of synaptic transmission was not observed at Schaffer collateral-CA1 synapses, while the submaximal tetanus now elicited frank LTD of synaptic EPSPs at perforant path synapses. These data suggest that prenatal morphine exposure enhances the susceptibility of entorhinal cortex to the induction of epileptiform activity, but shifts long-term plasticity of hippocampal synapses in favor of LTD.     

NCAM-antibodies modulate induction of long-term potentiation in rat hippocampal CA1

The neural cell adhesion molecule (NCAM) probably plays a role in neural plasticity in the adult vertebrate brain. We here present evidence that NCAM may be involved in long-term potentiation (LTP) in the CA1-region of rat hippocampal slices. It is shown that local application of antibodies against NCAM inhibits subsequent LTP-induction. Thus NCAM may be directly involved in the initial phase of LTP-induction. These results have important implications for the possible involvement of NCAM in learning and memory.     

Nicotine accelerates reversal of long-term potentiation and enhances long-term depression in the rat hippocampal CA1 region

In the hippocampal CA1 region, low-frequency stimulation (LFS; 200 pulses at 1 Hz) causes reversal of long-term potentiation (depotentiation, DP) and long-term depression (LTD), both of which are thought to be the cellular substrate of learning and memory. Because nicotine enhances learning and memory, we examined if nicotine modulates DP and LTD in the hippocampal CA1 region. Bath application of nicotine during LFS accelerated DP, that is, potentiated synaptic responses in hippocampal CA1 neurons returned to pre-tetanic control levels more rapidly in the presence of nicotine. Because a similar acceleration of DP was observed using the alpha7 nicotinic acetylcholine receptor (nAChR)-selective antagonist methyllcaconitine (MLA), the nicotine effect appeared to be at least partly mediated by nicotine-induced desensitization of alpha7 nAChRs. Delivery of LFS in the presence of nicotine or MLA also depressed synaptic responses in a naive pathway and facilitated LTD, that is, the magnitude of LTD was larger when the drug was present during LFS. Thus, these results demonstrate that nicotine facilitates DP and LTD, which may represent, at least in part, the cellular mechanism underlying nicotine-induced cognitive enhancement.