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.     

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.     

Calcium signals in long-term potentiation and long-term depression

We describe postsynaptic Ca2+ signals that subserve induction of two forms of neuronal plasticity, long-term potentiation (LTP) and long-term depression (LTD), in rat hippocampal neurons. The common induction protocol for LTP, a 1-s, 50-Hz tetanus, generates Ca2+ increases of about 50-Hz in dendritic spines of CA1 neurons. These very large increases, measured using a low affinity indicator (Mg fura 5), were found only in the spines and tertiary dendrites, and were dependent upon influx through N-methyl-D-aspartate (NMDA) gated channels. High affinity Ca2+ indicators (e.g., fura 2) are unable to demonstrate these events. In acute slices, neighboring dendritic branches often showed very different responses to a tetanus, and in some instances, neighboring spines on the same dendrite responded differently. LTD in mature CA1 neurons was induced by a low frequency stimulus protocol (2 Hz, 900 pulses), in the presence of GABA- and NMDA-receptor blockers. This LTD protocol produced dendritic Ca2+ increases of <1 microM. Duration of the Ca2+ increase was approximately 30 s and was due to voltage-gated Ca2+ influx. Finally, the ability of synaptically addressed Ca2+ stores to release Ca2+ was studied in CA3 neurons and was found to require immediate preloading and high intensity presynaptic stimulation, conditions unlike normal LTP-LTD protocols.     

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).     

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.     

Direct measurement of quantal changes underlying long-term potentiation in CA1 hippocampus.

The modification responsible for the long-term synaptic potentiation (LTP) that follows a brief conditioning period is not known. To elucidate this change, we have resolved quantal levels of transmission before and after induction of LTP. We find an increase both in the number of quanta released and in quantal amplitude, consistent with combined pre- and postsynaptic modifications. On average, about 60% of LTP can be accounted for by presynaptic enhancement. The increase in either quantal amplitude or quantal content varies significantly among different experiments, but is inversely correlated with its initial value. These results may help to reconcile the different views concerning the site of LTP expression.     

Wip1 phosphatase modulates both long-term potentiation and long-term depression through the dephosphorylation of CaMKII

Synaptic plasticity is an important mechanism that underlies learning and cognition. Protein phosphorylation by kinases and dephosphorylation by phosphatases play critical roles in the activity-dependent alteration of synaptic plasticity. In this study, we report that Wip1, a protein phosphatase, is essential for long-term potentiation (LTP) and long-term depression (LTD) processes. Wip1-deletion suppresses LTP and enhances LTD in the hippocampus CA1 area. Wip1 deficiency-induced aberrant elevation of CaMKII T286/287 and T305 phosphorylation underlies these dysfunctions. Moreover, we showed that Wip1 modulates CaMKII dephosphorylation. Wip1^?/? mice exhibit abnormal GluR1 membrane expression, which could be reversed by the application of a CaMKII inhibitor, indicating that Wip1/CaMKII signaling is crucial for synaptic plasticity. Together, our results demonstrate that Wip1 phosphatase plays a vital role in regulating hippocampal synaptic plasticity by modulating the phosphorylation of CaMKII.     

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     

CaM kinase II and protein kinase C activations mediate enhancement of long-term potentiation by nefiracetam in the rat hippocampal CA1 region

Nefiracetam is a pyrrolidine-related nootropic drug exhibiting various pharmacological actions such as cognitive-enhancing effect. We previously showed that nefiracetam potentiates NMDA-induced currents in cultured rat cortical neurons. To address questions whether nefiracetam affects NMDA receptor-dependent synaptic plasticity in the hippocampus, we assessed effects of nefiracetam on NMDA receptor-dependent long-term potentiation (LTP) by electrophysiology and LTP-induced phosphorylation of synaptic proteins by immunoblotting analysis. Nefiracetam treatment at 1-1000 nM increased the slope of fEPSPs in a dose-dependent manner. The enhancement was associated with increased phosphorylation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor through activation of calcium/calmodulin-dependent protein kinase II (CaMKII) without affecting synapsin I phosphorylation. In addition, nefiracetam treatment increased PKCalpha activity in a bell-shaped dose-response curve which peaked at 10 nM, thereby increasing phosphorylation of myristoylated alanine-rich protein kinase C substrate and NMDA receptor. Nefiracetam treatment did not affect protein kinase A activity. Consistent with the bell-shaped PKCalpha activation, nefiracetam treatment enhanced LTP in the rat hippocampal CA1 region with the same bell-shaped dose-response curve. Furthermore, nefiracetam-induced LTP enhancement was closely associated with CaMKII and PKCalpha activation with concomitant increases in phosphorylation of their endogenous substrates except for synapsin I. These results suggest that nefiracetam potentiates AMPA receptor-mediated fEPSPs through CaMKII activation and enhances NMDA receptor-dependent LTP through potentiation of the post-synaptic CaMKII and protein kinase C activities. Together with potentiation of nicotinic acetylcholine receptor function, nefiracetam-enhanced AMPA and NMDA receptor functions likely contribute to improvement of cognitive function.     

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。     

Effects of the mono- and tetrasialogangliosides GM1 and GQ1b on ATP-induced long-term potentiation in hippocampal CA1 neurons

The effects of the mono- and tetrasialogangliosides, GM1 and GQ1b, on ATP-induced long-term potentiation (LTP) were studied in CA1 neurons of guinea pig hippocampal slices. Application of 5 or 10 microM ATP for 10 min resulted in a transient depression followed by a slow augmentation of synaptic transmission, leading to LTP. LTP induced by treatment with 5 microM ATP was facilitated in hippocampal slices prepared from animals treated for 6 days with a ceramide analog, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propranol, which stimulates ganglioside biosynthesis. In addition, LTP induced by 5 microM ATP was significantly enhanced when naive slices were incubated with GQ1b but not with GM1. These results suggest that a cooperative effect between extracellular ATP and GQ1b enhances ATP-induced LTP in hippocampal CA1 neurons. In addition, the LTP induced by 10 microM ATP was blocked by coapplication of the NMDA antagonist AP5 (5 microM or 50 microM), and this effect was partially inhibited by GQ1b pretreatment of the slices, suggesting that in hippocampal CA1 neurons, the enhancing effect of GQ1b on ATP-induced LTP is mediated by modulation of NMDA receptors/Ca(2+) channels.     

Interaction between interferon gamma and insulin-like growth factor-1 in hippocampus impacts on the ability of rats to sustain long-term potentiation

There is compelling evidence to suggest that inflammation significantly contributes to neurodegenerative changes. Consistent with this is the observation that several neurodegenerative disorders are accompanied by an increase in the concentration of interleukin (IL)-1beta. IL-1beta has a negative impact on synaptic plasticity and therefore an increased concentration of IL-1beta, such as that in the hippocampus of the aged rat, is associated with a deficit in long-term potentiation (LTP). IL-1beta is derived mainly from activated microglia but the trigger leading to this activation, specifically in the aged brain, remains to be identified. Here we examined the possibility that interferon (IFN)gamma may stimulate microglial activation and increase IL-1beta concentration, thereby inhibiting LTP. The IFNgamma concentration was increased in hippocampus prepared from aged, compared with young, rats and inversely correlated with the ability of rats to sustain LTP. Intracerebroventricular injection of IFNgamma inhibited LTP, and increased microglial activation was observed in both IFNgamma-injected and aged rats. The age-related increase in IFNgamma was accompanied by a decrease in the hippocampal concentration of insulin-like growth factor (IGF)-1. The evidence presented suggests that IGF-1 acts to antagonize the IFNgamma-induced microglial activation, the accompanying increase in IL-1beta concentration and the consequent deficit in LTP.     

Effects of matrix metalloproteinase inhibition on short- and long-term plasticity of schaffer collateral/CA1 synapses

It is increasingly evident that matrix metalloproteinases (MMPs), a family of zinc containing extracellular endopeptidases, participate in processes supporting hippocampal synaptic plasticity. The purpose of this study was to further the understanding of MMPs involvement in hippocampal plasticity. Acute hippocampal slices, generated from 20- to 30-day-old male Sprague-Dawley rats, were subjected to various electrophysiologic stimulatory paradigms to produce either short-term or long-term modifications to synaptic efficacy. Slices exposed to broad-spectrum MMP inhibitor, FN-439, exhibited impairments in paired-pulse facilitation, theta-burst facilitation, and long-term depression. Additionally, we observed that MMP inhibition impaired both the induction and stability of long-term potentiation (LTP). Furthermore, evidence indicated that the effect of MMP inhibition on LTP maintenance is dependent upon integrin-directed adhesion, whereas the effects of MMP inhibition on LTP induction are independent of integrin-directed adhesion. Together, these data support a generalized role for MMPs in short-term and long-term hippocampal plasticity and indicate that MMPs are a necessary facet of integrin-mediated cell adhesion supporting LTP stabilization.     

Interaction between the keratin cytoskeleton and eEF1Bgamma affects protein synthesis in epithelial cells

Eukaryotic elongation factor-1 (eEF1) is essential for peptide-chain elongation during translation. We report that its gamma subunit (eEF1Bgamma) specifically binds, and bundles, keratin intermediate filaments. Disrupting this interaction depresses translation by approximately 20% and selectively increases 80S ribosomes in epithelial cells, an outcome recapitulated by RNA interference-mediated silencing of eEF1Bgamma. These findings extend the emerging relationship between keratin proteins and the translational machinery.     

Calcium requirement of long-term depression and rebound potentiation in cerebellar Purkinje neurons

Cerebellar Purkinje neurons (PNs) receive two main excitatory inputs, from climbing fibers and parallel fibers, and inhibitory inputs, from GABAergic interneurons. The synapses formed by parallel fibers and by inhibitory interneurons on PNs are able to undergo long-lasting in efficacy. Thus, the excitatory parallel fiber-PN synapse undergoes long-term fibers. Synaptic inhibition can be potentiated by climbing fiber activity by a mechanism named rebound potentiation, resulting in a more powerful inhibitory effect of GABAergic interneurons. The induction of both long-term depression and rebound potentiation requires a transient elevation of the cytoplasmic calcium concentration ([Ca²⁺]_i). The [Ca²⁺]_i-transient is caused by Ca²⁺ entry through voltage-gated Ca²⁺ channels and, possibly, by release of Ca²⁺ from IP_3- and ryanodine-sensitive stores. Direct Ca²⁺ entry through synaptic AMPA receptor channels seems not to contribute significantly to the Ca²⁺ signal mediating the induction of both long-term depression and rebound potentiation.     

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.     

Staufen1 regulation of protein synthesis-dependent long-term potentiation and synaptic function in hippocampal pyramidal cells

Staufen1 (Stau1) is an RNA-binding protein involved in transport, localization, decay, and translational control of mRNA. In neurons, it is present in cell bodies and also in RNA granules which are transported along dendrites. Dendritic mRNA localization might be involved in long-term synaptic plasticity and memory. To determine the role of Stau1 in synaptic function, we examined the effects of Stau1 down-regulation in hippocampal slice cultures using small interfering RNA (siRNA). Biolistic transfection of Stau1 siRNA resulted in selective down-regulation of Stau1 in slice cultures. Consistent with a role of Stau1 in transporting mRNAs required for synaptic plasticity, Stau1 down-regulation impaired the late form of chemically induced long-term potentiation (L-LTP) without affecting early-LTP, mGluR1/5-mediated long-term depression, or basal evoked synaptic transmission. Stau1 down-regulation decreased the amplitude and frequency of miniature excitatory postsynaptic currents, suggesting a role in maintaining efficacy at hippocampal synapses. At the cellular level, Stau1 down-regulation shifted spine shape from regular to elongated spines, without changes in spine density. The change in spine shape could be rescued by an RNA interference-resistant Stau1 isoform. Therefore, Stau1 is important for processing and/or transporting in dendrites mRNAs that are critical in regulation of synaptic strength and maintenance of functional connectivity changes underlying hippocampus-dependent learning and memory.