Temporal pattern sensitivity of long-term potentiation in hippocampal CA1 neurons

High-frequency electrical stimulation in the hippocampus leads to an increase in synaptic efficacy that lasts for many hours. This long-term potentiation (LTP) of synaptic transmission is presumed to play a crucial role in learning and memory in the brain. However, the frequency of stimulation generally used to obtain LTP is beyond the normal physiological range of activity of hippocampal neurons. We found that LTP can be induced by an electrical stimulation whose frequency is comparable to that of the naturally occurring firing activity of hippocampal neurons if the stimulating pulseinterval train has a special time structure. In the present experiment, we compared the magnitude of LTP induced by the four types of stimuli which have the same pulse number and the same mean frequency but different time structure in interstimulus intervals. One type of stimuli has regular intervals, and this served as a control stimulus. In the other three types of stimuli, the adjacent interstimulus interval had the following statistical properties: in type 1, their correlations are positive; in type 2, negative; and in type 3, independent. The magnitude of LTP induced by these four types of stimuli showed clear order relationships: type 3/type 1 control > type 2. Detailed analysis of the evoked potential during a period of temporal pattern stimulation revealed that the amplitude of the population spikes of repetitive firing, especially of the second and third population spikes, had the same order relationship as the LTP. Because 2-amino-5-phosphonovalerate (APV) (50 M) selectively abolished the second and the third population spikes but not the first, and blocked the formation of LTP, the second and the third peaks which appeared as part of the late component of excitatory postsynaptic potentials (EPSP) must involve LTP formation through the activities of N-methy-D-aspartate (NMDA) channels. From the experimental data, a dynamic induction rule concerning LTP in specific neural networks was derived by which the temporal information of the input stimuli can be extracted and transformed into the weight space of synaptic connections in hippocampal networks (see Fig. 1. CA1).     

Two dynamic processes for the induction of long-term potentiation in hippocampal CA1 neurons

This work sets out to investigate fast and slow dynamic processes and how they effect the induction of long-term potentiation (LTP). Functionally, the fast process will work as a time window to take a spatial coincidence among various inputs projected to the hippocampus, and the slow process will work as a temporal integrator of a sequence of dynamic events. Firstly, the two factors were studied using a “burst” stimulus and a “long-interval patterns” stimulus. Secondly, we propose that, for the induction of LTP, there are two dynamic processes, fast and slow, which are productively activated by bursts and long-interval patterns. The model parameters, a time constant of short dynamics and one of long dynamics, were determined by fitting the values obtained from model simulation to the experimental data. A molecular factor or cellular factors with these two time constants are likely to be induced in LTP induction. Received: 3 November 1997 / Accepted in revised form: 18 August 1999     

Leptin reverses long-term potentiation at hippocampal CA1 synapses

The hormone leptin crosses the blood brain barrier and regulates numerous neuronal functions, including hippocampal synaptic plasticity. Here we show that application of leptin resulted in the reversal of long-term potentiation (LTP) at hippocampal CA1 synapses. The ability of leptin to depotentiate CA1 synapses was concentration-dependent and it displayed a distinct temporal profile. Leptin-induced depotentiation was not associated with any change in the paired pulse facilitation ratio or the coefficient of variance, indicating a post-synaptic locus of expression. Moreover, the synaptic activation of NMDA receptors was required for leptin-induced depotentiation as the effects of leptin were blocked by the competitive NMDA receptor antagonist, D-aminophosphovaleric acid (D-AP5). The signaling mechanisms underlying leptin-induced depotentiation involved activation of the calcium/calmodulin-dependent protein phosphatase, calcineurin, but were independent of c- jun NH₂ terminal kinase. Furthermore, leptin-induced depotentiation was accompanied by a reduction in α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor rectification indicating that loss of glutamate receptor 2 (GluR2)-lacking AMPA receptors underlies this process. These data indicate that leptin reverses hippocampal LTP via a process involving calcineurin-dependent internalization of GluR2-lacking AMPA receptors which further highlights the key role for this hormone in regulating hippocampal synaptic plasticity and neuronal development.     

Chaotic stimulus dependent long-term potentiation in the hippocampal CA1 area

In our previous report [Tsukada, M., Aihara, T., Saito, H., Kato, H., 1996. Neural Netw. 9, 1357-1365], the temporal pattern sensitivity of long-term potentiation (LTP) in hippocampal CA1 neurons was estimated by using Markov chain stimuli (MS) with different values of the serial correlation coefficient rho1 between successive interstimulus-intervals. In this paper, the effect of chaotic stimuli (CS) on induction of LTP in the hippocampal CA1 area was investigated in comparison with that of MS and periodic pattern stimuli (PS). The CS were produced by a modified Bernoulli map, so that interstimulus sequences with various values of rho1 can be generated by changing the parameter B. These stimuli had an identical first order statistics (mean interstimulus-interval), but their higher order statistics such as the serial correlation coefficients were different. The LTP induced by CS at B = 2 was significantly larger in magnitude than that of PS and MS, and also depended on the initial value of CS at B = 2 and 3. These results suggest that chaotic signals play an important role for memory coding in the hippocampal CA1 network.     

Effects of Chronic Stress and Phenytoin on the Long-term Potentiation （LTP） in Rat Hippocampal CA1 Region

Stress is the response to stimulation from inside andoutside with complicated effects on organisms. Appropri-ate stressful reactions are helpful in resisting diseases byactivating unspecific modulation system, while severe orprolonged stresses are harmful and even induce mentaland physical disorders such as recurrent depression, post-traumatic stress disorder (PTSD), Alzheimer’s disease andepilepsy [1]. Hippocampus, a main brain region of keyimportance for learning, memory and emotion, is t…     

低频刺激诱发海马突触传递去长时程增强的特性研究

目的和方法：以频率为1、3或5Hz,脉冲数为300或900,与高频刺激（HFS）时间间隔是20min或100min的低频刺激（LFS）作用于大鼠海马脑片,分别观察其对CA1区突触传递去长时程增强（DP）形成的影响。结果：HFS（100Hz,100脉冲的串刺激两串,串间隔30s)可诱发突触传递效率的长时程增强（LTP）。HFS经20min给予3Hz900脉冲的LFS可翻转LTP,产生DP,该作用可为NMDA受体阻断剂AP5（50μmol/L)所阻断,1Hz、5Hz、低脉冲数或与HFS时间间隔长的LFS,其诱发DP的效率减弱。结论：诱发海马CA1区DP的产生,对LFS的参数有较强的依从性。该作用可能是通过激活NMDA受体而实现的。     

Gangliosides GM1 and GD1b are not polarized in mature hippocampal neurons.

Analysis of the binding of cholera toxin to ganglioside GM1 in both living and fixed neurons, and comparison with the distribution of defined axonal and dendritic proteins, demonstrates that ganglioside GM1 is distributed in a non-polarized manner over the axonal and dendritic plasma membranes of mature, cultured hippocampal neurons. Likewise, ganglioside GD1b is also distributed in a non-polarized manner. These results suggest that a recent report [Ledesma, M.D. et al. EMBO J. 18 (1999) 1761-1771] proposing that ganglioside GM1 is highly enriched on the axonal versus dendritic membrane of hippocampal neurons may need to be re-evaluated.     

Low intensity tetanic stimulation induces long-term potentiation in hippocampal neurons

A minimal intensity of the stimulation necessary for the induction of long-term potentiation of synaptic transmission (LTP) was investigated by intracellular recording in guinea pig in vitro hippocampal slices. High frequency stimulation of afferent fibres at intensities evoking in CA 1 neurons control excitatory postsynaptic potentials (EPSPs) of amplitudes 1-5 mV, resulted usually in a long-lasting increase in response amplitude. LTP was not observed at lower stimulus strength. The coactivation of a certain, though small number of synaptic contacts is thus necessary for the production of LTP.     

Coincident activity of converging pathways enables simultaneous long-term potentiation and long-term depression in hippocampal CA1 network in vivo

Memory is believed to depend on activity-dependent changes in the strength of synapses, e.g. long-term potentiation (LTP) and long-term depression (LTD), which can be determined by the sequence of coincident pre- and postsynaptic activity, respectively. It remains unclear, however, whether and how coincident activity of converging efferent pathways can enable LTP and LTD in the pathways simultaneously. Here, we report that, in pentobarbital-anesthetized rats, stimulation (600 pulses, 5 Hz) to Schaffer preceding to commissural pathway within a 40-ms timing window induced similar magnitudes of LTP in both pathways onto synapses of CA1 neurons, with varied LTP magnitudes after reversal of the stimulation sequence. In contrast, in urethane-anesthetized or freely-moving rats, the stimulation to Schaffer preceding to commissural pathway induced Schaffer LTP and commissural LTD simultaneously within a 40-ms timing window, without affecting synaptic efficacy in the reversed stimulation sequence. Coincident activity of Schaffer pathways confirmed the above findings under pentobarbital and urethane anesthesia. Thus, coincident activity of converging afferent pathways tends to switch the pathways to be LTP only or LTP/LTD depending on the activity states of the hippocampus. This network rule strengthens the view that activity-dependent synaptic plasticity may well contribute to memory process of the hippocampal network with flexibility or stability from one state to another.     

双电极绑定技术记录在体大鼠海马CA1区长时程增强

目的:探讨双电极绑定条件下记录大鼠在体海马CA1区长时程增强的可行性。方法:雄性Wistar大鼠乌拉坦麻醉;脑立体定位仪上埋置脑室导管;安装自制的刺激/记录绑定电极;引导基础性场兴奋性突触后电位(fEP-SP);强直刺激诱导长时程增强(LTP)。结果:绑定后的刺激和记录电极能可靠地引起海马CA1区fEPSP,fEPSP的出现率几乎100%;基础性fEPSP记录可保持长时间稳定;高频刺激成功诱导出LTP并维持达3h以上,诱导率约67%;双脉冲易化记录稳定、可靠;脑室注射β淀粉样蛋白(Aβ)对LTP显示出明显的压抑作用。结论:采用双电极绑定技术进行在体海马LTP记录简便易行、节省资源、引导fEPSP和诱导LTP的成功率较高,有望成为一项重要的研究学习和记忆机制的电生理辅助手段。     

Biosynthesis of glycerol phosphate is associated with long-term potentiation in hippocampal neurons

Introduction

Neurons have a very high energy requirement, and their metabolism is tightly regulated to ensure delivery of adequate substrate to sustain neuronal activity and neuroplastic changes. The mechanisms underlying the regulation of neuronal metabolism, however, are not completely clear.

Objective

The objective of this study was to investigate the central carbon metabolism in neurons, in order to identify the regulatory pathways governing neuronal anabolism and catabolism.

Methods

Here we first have applied MS-based endometabolomics to elucidate the metabolic dynamics in cultured hippocampal primary neurons. Using nanoLC-ESI-LTQ Orbitrap MS approach followed by statistical analysis, we measure the dynamics of uniformly labeled ¹³C-glucose entering neurons. We adapted the method by coupling offline patch-clamp setup with MS to confirm findings in vivo.

Results

According to non-parametric statistical analysis of metabolic dynamics, in cultured hippocampal neurons, the glycerol phosphate shuttle is active and correlates with the metabolic flux in the pentose phosphate pathway. In the hippocampus, glycerol-3-phosphate biosynthesis was activated in response to long-term potentiation together with the upregulation of glycolysis and the TCA cycle, but was inactive or silenced in basal conditions.

Conclusions

We identified the biosynthesis of glycerol-3-phosphate as a key regulator in mechanisms implicated in learning and memory. Notably, defects in enzymes linked with the glycerol phosphate shuttle have been implicated in neurological disorders and intellectual disability_. These results could improve our understanding of the general mechanisms of learning and memory and facilitate the development of novel therapies for metabolic disorders linked with intellectual disability.

     

Dose-dependent effects of phencyclidine on hippocampal CA1 neurons

The dose-dependent effects of phencyclidine were examined in guinea pig hippocampal slices using intracellular and extracellular recordings. Orthodromically evoked population potentials from the CA1 cell body layer were enhanced by low doses (0.2-0.4 microM) and depressed by high doses (0.01-10 mM). Medium doses of the drug (2.0-10.0 microM) showed little effect. Intracellular recordings from CA1 pyramidal neurons gave similar dose-dependent results. Low doses increased spontaneous firing rates and caused silent cells to fire. Medium doses both increased and decreased firing rates, whereas high doses depressed firing rates. Large transient depolarizing shifts were seen in some phencyclidine-treated cells at medium and high doses. Phencyclidine effects took 15-30 min to develop and were only partially reversible after a washout of up to 1 h.     

Increased retention of calcium in the dendrites of long-term potentiated CA1 neurons of the hippocampal slice

Summary In view of the importance of calcium in the induction of long-term potentiation (LTP), experiments were carried out to localize calcium at the electron microscopic level in the CA1 region of guinea pig hippocampal slices, following high-frequency stimulation of the Schaffer collaterals. Apart from the ultrastructural localization, a semiquantitative method was used to count the calcium-containing deposits in electron micrographs. Significantly more calcium-containing deposits were seen in the dendrites of the stratum radiatum in slices with LTP than in those without it. A moderate increase of the extradendritic deposits was observed, too. The calcium content of the deposits was determined by means of EGTA incubation and X-ray analysis. The presented results, together with the relevant literature data, underline the importance of calcium-activated processes in postsynaptic structures probably involved in the generation of LTP.     

Taurine-evoked chloride current and its potentiation by intracellular Ca2+ in immature rat hippocampal CA1 neurons

Taurine is one of the most abundant free amino acids in the immature mammalian central nervous system. In the present study, whole-cell patch-clamp recordings were made to examine taurine-evoked currents ( I(Tau)) in acutely dissociated immature rat hippocampal CA1 neurons. Taurine at low concentrations (/=3 mM) activated both glycine and GABA(A) receptors. Moreover, elevation of intracellular Ca(2+) via non-NMDA receptor activation enhanced I(Tau) reversibly. The results indicate that taurine may act as a native ligand of glycine receptors and modulate neurotransmissions in the immature hippocampus, and under certain conditions it can also activate GABA(A) receptors. The potentiation of I(Tau) by intracellular Ca(2+) may contribute to the protection effect of taurine under some cell-damaging conditions.     

Brevican-deficient mice display impaired hippocampal CA1 long-term potentiation but show no obvious deficits in learning and memory

Brevican is a brain-specific proteoglycan which is found in specialized extracellular matrix structures called perineuronal nets. Brevican increases the invasiveness of glioma cells in vivo and has been suggested to play a role in central nervous system fiber tract development. To study the role of brevican in the development and function of the brain, we generated mice lacking a functional brevican gene. These mice are viable and fertile and have a normal life span. Brain anatomy was normal, although alterations in the expression of neurocan were detected. Perineuronal nets formed but appeared to be less prominent in mutant than in wild-type mice. Brevican-deficient mice showed significant deficits in the maintenance of hippocampal long-term potentiation (LTP). However, no obvious impairment of excitatory and inhibitory synaptic transmission was found, suggesting a complex cause for the LTP defect. Detailed behavioral analysis revealed no statistically significant deficits in learning and memory. These data indicate that brevican is not crucial for brain development but has restricted structural and functional roles.     

Leptin facilitates learning and memory performance and enhances hippocampal CA1 long-term potentiation and CaMK II phosphorylation in rats

Leptin, an adipocytokine encoded by an obesity gene and expressed in adipose tissue, affects feeding behavior, thermogenesis, and neuroendocrine status via leptin receptors distributed in the brain, especially in the hypothalamus. Leptin may also modulate the synaptic plasticity and behavioral performance related to learning and memory since: leptin receptors are found in the hippocampus, and both leptin and its receptor share structural and functional similarities with the interleukin-6 family of cytokines that modulate long-term potentiation (LTP) in the hippocampus. We therefore examined the effect of leptin on (1) behavioral performance in emotional and spatial learning tasks, (2) LTP at Schaffer collateral-CA1 synapses, (3) presynaptic and postsynaptic activities in hippocampal CA1 neurons, (4) the intracellular Ca(2+) concentration ([Ca(2+)](i)) in CA1 neurons, and (5) the activity of Ca(2+)/calmodulin protein kinase II (CaMK II) in the hippocampal CA1 tissue that exhibits LTP. Intravenous injection of 5 and/or 50mug/kg, but not of 500mug/kg leptin, facilitated behavioral performance in passive avoidance and Morris water-maze tasks. Bath application of 10(-12)M leptin in slice experiments enhanced LTP and increased the presynaptic transmitter release, whereas 10(-10)M leptin suppressed LTP and reduced the postsynaptic receptor sensitivity to N-methyl-d-aspartic acid. The increase in the [Ca(2+)](i) induced by 10(-10)M leptin was two times greater than that induced by 10(-12)M leptin. In addition, the facilitation (10(-12)M) and suppression (10(-10)M) of LTP by leptin was closely associated with an increase and decrease in Ca(2+)-independent activity of CaMK II. Our results show that leptin not only affects hypothalamic functions (such as feeding, thermogenesis, and neuroendocrine status), but also modulates higher nervous functions, such as the behavioral performance related to learning and memory and hippocampal synaptic plasticity.     

Effects of adrenal steroids and their reduced metabolites on hippocampal long-term potentiation

We studied the effects of steroid hormones on the hippocampal long-term potentiation (LTP), a putative mechanism of neuronal plasticity and memory storage in the CNS. In vivo experiments were performed in rats under chloral hydrate anesthesia (0.4 mg/kg i.p.). All animals were adrenalectomized 48 h before recording. LTP was induced after priming tetanic stimulation at the perforant pathway (PP) and single pulse field potentials were obtained from the dentate gyrus (DG). The excitatory post-synaptic potential (EPSP) slope and population spike (PS) amplitude were analyzed before and after the i.v. injection of the steroids and after the induction of LTP, and followed up to 1 h. Results obtained with the hormones were compared with matched control animals injected with vehicle alone, Nutralipid 10%. Previous results from our laboratory showed that deoxycorticosterone (DOC) decreased the magnitude of the EPSP at all times after priming stimulation and the PS decreased during the first 30 min of the LTP. Corticosterone decreased the EPSP in the first 15 min and the PS during the first 30 min after priming stimuli. In these experiments the mineralocorticoids aldosterone and 18-OH-DOC elicited a decrease of the EPSP at all times post-train; and no significant difference against vehicle was observed in the PS. Post-injection values were not changed except for 18-OH-DOC at a dose of 1 mg, where a decrease of both the EPSP (P less than 0.01) and the PS (P less than 0.02) was observed against vehicle. ATH-progesterone at 0.1 mg/rat also decreased the EPSP values significantly after priming stimulation and no significant changes against vehicle were observed in the PS. These results show that adrenal steroids can modulate hippocampal LTP, that they can act at different neuronal loci and with different time courses in the development of the phenomena.     

焦亚硫酸钠对大鼠海马CA1区神经元钾电流的影响

目的:探讨焦亚硫酸钠(SMB)、二氧化硫(SO2)及其体内衍生物(亚硫酸盐和亚硫酸氢盐)对中枢神经元钾通道的影响及超氧化物歧化酶(SOD)、过氧化氢酶(CAT)及谷胱甘肽过氧化物酶(GPx)相应的保护作用.方法:采用全细胞膜片钳技术研究了SMB对大鼠海马CA1区神经元瞬间外向钾电流(IA)和延迟整流钾电流(IK)的影响.结果:①焦亚硫酸钠可增大全细胞IA和IK,且具剂量依赖性和电压依赖性,使IA和IK增大50%的剂量分别为15.8 μmol/L和11.5μmol/L;②10 μmol/L的SMB均可显著影响IA和IK的激活过程,给药前后IA的半数激活电压分别为(-12.6±1.6)mV和(-7.0±1.3)mV(n=8,P＜0.01),IK的半数激活电压分别为(10.8±0.9)mV和(21.6±0.7)mV(n=8,P＜0.01),但不改变其斜率因子;③10μmol/L的SMB还非常显著地影响IA的失活过程,给药前后其半数失活电压分别为(-97.0±1.1)mV和(-84.4±3.3)mV(n=8,P＜0.01),但也不改变其斜率因子;④抗氧化酶SOD(1×106U/L)、CAT(2×106U/L)及GPx(105U/L)均可使SMB(10μmol/L)增大的IA和IK部分恢复.结论:SMB可显著增大IA和IK,抑制IA和IK的激活过程及IA的失活过程,从而导致胞内K 的外流增加,使胞内K 浓度降低,从而对中枢神经元功能产生不利影响.     

Serotonin agonist and antagonist actions in hippocampal CA1 neurons

The actions of serotonin (5-HT) and its putative agonists and antagonists were examined in vitro on hippocampal CA1 neurons using intracellular recordings, demonstrating that the cellular pharmacological effects can not necessarily be predicted from binding characteristics alone. The first response following 5-HT application was often a long-lasting (several minutes) hyperpolarization associated with decreased input resistance. Subsequent 5-HT applications caused only brief hyperpolarizations (30-120 s) and associated decreased input resistance, often followed by membrane depolarization. The post-spike train afterhyperpolarization (AHP) was prolonged for several minutes following the 5-HT induced hyperpolarization. 5-HT1 agonists (8-hydroxy-2-(di-n-propylamino)tetralin, 5-methoxytryptamine, MK-212) caused a prolonged hyperpolarization, decreased input resistance, and enhancement of the AHP. 5-HT applied following agonist application elicited only short-lasting hyperpolarizations. The 5-HT2 antagonists, cyproheptadine and mianserin, and a nonspecific 5-HT antagonist, methysergide, also caused a prolonged hyperpolarization with decreased input resistance. Spiperone, a nonspecific 5-HT antagonist, and ritanserin, a putative specific 5-HT2 receptor antagonist, depolarized CA1 neurons with little or no change in input resistance. The 5-HT-induced short-lasting hyperpolarization was not affected by drop application of 5-HT antagonists, except for methysergide, but perfusion of methysergide, ritanserin, and spiperone attenuated this response. The long-lasting 5-HT hyperpolarization might be mediated by 5-HT1A receptor activation, and the short-lasting hyperpolarization by another serotonergic receptor subtype.