Long-term Potentiation In Synapses Research Articles

Long-term potentiation at pyramidal cell to somatostatin interneuron synapses controls hippocampal network plasticity and memory

SummaryHippocampal somatostatin (SOM) cells are dendrite-projecting inhibitory interneurons. CA1 SOM cells receive major excitatory inputs from pyramidal cells (PC-SOM synapses) which show mGluR1a- and mTORC1-mediated long-term potentiation (LTP). PC-SOM synapse LTP contributes to CA1 network metaplasticity and memory consolidation, but whether it is sufficient to regulate these processes remains unknown. Here we used optogenetic stimulation of CA1 pyramidal cells and whole-cell recordings in slices to show that optogenetic theta-burst stimulation (TBSopto) produces LTP at PC-SOM synapses. At the network level, we found that TBSopto differentially regulates metaplasticity of pyramidal cell inputs: enhancing LTP at Schaffer collateral synapses and depressing LTP at temporo-ammonic synapses. At the behavioral level, we uncovered that in vivo TBSopto regulates learning-induced LTP at PC-SOM synapses, as well as contextual fear memory. Thus, LTP of PC-SOM synapses is a long-term feedback mechanism controlling pyramidal cell synaptic plasticity, sufficient to regulate memory consolidation.

Calmodulin acetylation: A modification to remember

The formation of new memories appears to require alterations in the shape and strength of synapses within the hippocampus, yet our knowledge of the molecular mechanisms underlying these changes remains incomplete. Zhang and colleagues provide new understanding of memory formation by uncovering the lysine acetyltransferase SRC3 as the key driver of the novel posttranslational modification of calmodulin (CaM) acetylation, which regulates CaM's activity and subsequent activation of CaMKII. This new pathway is demonstrated to be both necessary and sufficient for CA3→CA1 synapse long-term potentiation (LTP) and fear memory formation, and this approach may act as a blueprint for future investigation of the role of acetylation of other proteins in neuronal functions.

Memory Improving Effects in Social-Isolated Aged Rats by Seaweed Glycoproteins

Social isolation and loneliness that could induce cognitive decline are serious public health problems in elderly. The trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is a critical process in long-term potentiation of synapses that is necessary for memory formation. We previously found that glycoproteins of an edible seaweed Capsosiphon fulvescens (C. fulvescens) prevent aging-induced cognitive impairment via regulation of brain-derived neurotrophic factor in hippocampus. This study was to investigate whether chronic administration of hydrophilic glycoproteins of C. fulvescens (Cf-hGP) prevent cognitive dysfunctions caused by social isolation in aged rats and this effect is regulated by post synaptic density protein 95 (PSD-95)-mediated AMPAR trafficking and the glycosylation of Cf-hGP. Social isolation for four weeks decreased phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2), PSD-95 (Ser295) and AMPAR GluR1 (Ser845) and increased expression of metabotropic glutamate receptor 5 (mGluR5) in synaptosome of the dorsal hippocampus, which was attenuated by chronic Cf-hGP treatment (15 mg/kg/day, 4 weeks). Blockade of mGluR5 abolished decrease in ERK1/2-mediated phosphorylation of PSD-95 (Ser295) and GluR1 (Ser845) in the socially isolated rats. In particular, chronic Cf-hGP treatment enhanced binding of ERK1/2 to PSD-95 and upregulated the surface movement of AMPAR GluR1 in the dorsal hippocampus. In addition, Cf-hGP treatment prevented spatial memory impairment caused by the social isolation, which was attenuated by inhibition of ERK1/2 or deglycosylation of Cf-hGP. These findings suggest that Cf-hGP-induced clustering of ERK1/2-mediated PSD-95 in the dorsal hippocampus improves memory formation in socially isolated aged rats and protein glycosylation contributes to enhancing the Cf-hGP effect.

Modeling on Heterosynaptic Plasticity Based on Postsynaptic Membrane Potential and Current Density

It is still elusive whether different regions in pyramidal neurons have the same heterosynaptic plasticity. To explain the heterosynaptic plasticity, we created a model of synaptic plasticity in which synaptic changes depend on the postsynaptic membrane potential and current density. We found that, in a simulated L5 pyramidal neuron, LTP (long-term potentiation) of synapses in each region of the neuron leads to LTD (long-term depression) of synapses in other regions, which is consistent with the experimental results of heterosynaptic plasticity. However, the effects of heterosynaptic plasticity in different regions are different. Compared with the basal and apical regions, LTP of synapses in the tuft region can not induce significant LTD in other regions. Our research provides a new way to solve the runaway growth of synaptic weights in a neural network.

Single Synapse LTP: A Matter of Context?

The most commonly studied form of synaptic plasticity is long-term potentiation (LTP). Over the last 15 years, it has been possible to induce structural and functional LTP in dendritic spines using two-photon glutamate uncaging, allowing for studying the signaling mechanisms of LTP with single synapse resolution. In this review, we compare different stimulation methods to induce single synapse LTP and discuss how LTP is expressed. We summarize the underlying signaling mechanisms that have been studied with high spatiotemporal resolution. Finally, we discuss how LTP in a single synapse can be affected by excitatory and inhibitory synapses nearby. We argue that single synapse LTP is highly dependent on context: the choice of induction method, the history of the dendritic spine and the dendritic vicinity crucially affect signaling pathways and expression of single synapse LTP.

Long-Term Potentiation of Prelimbic Cortex Ascribed to Heat-Sensitization Responses of Moxibustion.

Heat-sensitization responses occurred in certain patients while exposed to suspended moxibustion. The response often indicated that the efficacy of moxibustion to those with it tended to triumph over those without. However, its mechanism remains to be explained. Our previous fMRI and EEG studies confirmed the changes of activities in cerebral certain regions accompanied with heat-sensitization responses, especially in prefrontal cortex. Therefore, we hypothesize that neurological system is involved in moxibustion-induced heat-sensitization responses. In the present study, phosphorylation of Cofilin representing long-term potentiation in synapse of prelimbic cortex of medial prefrontal cortex in stroke rats over suspended moxibustion was assessed, and the size of phosphorylated Cofilin positive spine in synapse was also measured. The result showed that heat-sensitization responses were observed to augment cerebral ischemic stroke-induced phosphorylation of Cofilin in prelimbic cortex of rats and increase the numbers of large synapses. This indicated that long-term potentiation of prelimbic cortex was attributed to heat-sensitization responses that were certain neurological responses of medial prefrontal cortex to suspended moxibustion.

Hippocampal long-term potentiation that is elicited by perforant path stimulation or that occurs in conjunction with spatial learning is tightly controlled by beta-adrenoreceptors and the locus coeruleus.

ABSTRACTThe noradrenergic system, driven by locus coeruleus (LC) activation, plays a key role in the regulating and directing of changes in hippocampal synaptic efficacy. The LC releases noradrenaline in response to novel experience and LC activation leads to an enhancement of hippocampus‐based learning, and facilitates synaptic plasticity in the form of long‐term depression (LTD) and long‐term potentiation (LTP) that occur in association with spatial learning. The predominant receptor for mediating these effects is the β‐adrenoreceptor. Interestingly, the dependency of synaptic plasticity on this receptor is different in the hippocampal subfields whereby in the CA1 in vivo, LTP, but not LTD requires β‐adrenoreceptor activation, whereas in the mossy fiber synapse LTP and LTD do not depend on this receptor. By contrast, synaptic plasticity that is facilitated by spatial learning is highly dependent on β‐adrenoreceptor activation in both hippocampal subfields. Here, we explored whether LTP induced by perforant‐path (pp) stimulation in vivo or that is facilitated by spatial learning depends on β‐adrenoreceptors. We found that under both LTP conditions, antagonising the receptors disabled the persistence of LTP. β‐adrenoreceptor‐antagonism also prevented spatial learning. Strikingly, activation of the LC before high‐frequency stimulation (HFS) of the pp prevented short‐term potentiation but not LTP, and LC stimulation after pp‐HFS‐induced depotentiation of LTP. This depotentiation was prevented by β‐adrenoreceptor‐antagonism. These data suggest that β‐adrenoreceptor‐activation, resulting from noradrenaline release from the LC during enhanced arousal and learning, comprises a mechanism whereby the duration and degree of LTP is regulated and fine tuned. This may serve to optimize the creation of a spatial memory engram by means of LTP and LTD. This process can be expected to support the special role of the dentate gyrus as a crucial subregional locus for detecting and processing novelty within the hippocampus. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.

Stratum oriens stimulation‐evoked modulation of hippocampal long‐term potentiation involves the activation of muscarinic acetylcholine receptors and the inhibition of Kv7/M potassium ion channels

Acetylcholine is considered to be an endogenous modulator of hippocampal neurotransmission and synaptic plasticity. The activation of muscarinic acetylcholine receptors (mAChRs) reportedly enhances hippocampal synaptic plasticity, which plays an important role in memory function; however, the mechanism by which it enhances synaptic plasticity remains unclear. Here, we examined the involvement of the inhibition of Kv7/M K(+) channels, which are targets of mAChR modulation, during mAChR activation-induced enhancement of long-term potentiation (LTP) at rat hippocampal Schaffer collateral (SC)-CA1 synapses. When an electrical stimulus was applied to the stratum oriens before tetanic stimulation of the SCs, the magnitude of the induced SC-CA1 synapse LTP was enhanced as compared with that induced without stratum oriens stimulation. In the presence of the mAChR antagonist atropine, tetanic stimulation induced stable LTP, but the stratum oriens stimulation-evoked enhancement of LTP was abolished. The additional application of XE991, a selective blocker of Kv7/M K(+) channels, rescued the atropine-induced inhibition of LTP enhancement. The phospholipase C (PLC) inhibitor U-73122 inhibited the stratum oriens stimulation-evoked enhancement of LTP. Application of the T/R-type voltage-dependent Ca(2+) channel (VDCC) blocker Ni(2+) abolished the stratum oriens stimulation-evoked enhancement of LTP. In addition, tetanic stimulation with preceding stratum oriens stimulation was able to induce LTP during N-methyl-d-aspartate receptor blockade. We therefore propose that stratum oriens stimulation inhibits Kv7/M K(+) channels through mAChR activation-induced PLC activation, which leads to VDCC activation, and hence causes sufficient Ca(2+) influx to enhance LTP.

Summation in the Hippocampal CA3-CA1 Network Remains Robustly Linear Following Inhibitory Modulation and Plasticity, but Undergoes Scaling and Offset Transformations

Many theories of neural network function assume linear summation. This is in apparent conflict with several known forms of non-linearity in real neurons. Furthermore, key network properties depend on the summation parameters, which are themselves subject to modulation and plasticity in real neurons. We tested summation responses as measured by spiking activity in small groups of CA1 pyramidal neurons using permutations of inputs delivered on an electrode array. We used calcium dye recordings as a readout of the summed spiking response of cell assemblies in the network. Each group consisted of 2–10 cells, and the calcium signal from each cell correlated with individual action potentials. We find that the responses of these small cell groups sum linearly, despite previously reported dendritic non-linearities and the thresholded responses of individual cells. This linear summation persisted when input strengths were reduced. Blockage of inhibition shifted responses up toward saturation, but did not alter the slope of the linear region of summation. Long-term potentiation of synapses in the slice also preserved the linear fit, with an increase in absolute response. However, in this case the summation gain decreased, suggesting a homeostatic process for preserving overall network excitability. Overall, our results suggest that cell groups in the CA3-CA1 network robustly follow a consistent set of linear summation and gain-control rules, notwithstanding the intrinsic non-linearities of individual neurons. Cell-group responses remain linear, with well-defined transformations following inhibitory modulation and plasticity. Our measures of these transformations provide useful parameters to apply to neural network analyses involving modulation and plasticity.

Molecular identification and expression of the NMDA receptor NR1 subunit in the leech

The N-methyl-D-aspartate receptor (NMDAR) is involved in a number of physiological and pathophysiological processes in vertebrates, but there have been few studies examining the role of invertebrate NMDA receptors. In the leech, pharmacological evidence suggests that NMDARs contribute to synaptic plasticity, but there has been no molecular identification of NMDA receptors. In this report, a partial cDNA encoding the leech NR1 subunit of the NMDA receptor (HirNR1) is presented. Reverse transcriptase-polymerase chain reaction from single neurons of the leech central nervous system confirms HirNR1 expression in the Retzius (R), Anterior Pagoda (AP), Pressure (P), and Touch (T) neurons. Immunoblotting with an anti-NR1 antibody yielded a approximately 110 kDa protein, similar to the expected weight of the NR1 subunit (approximately 116 kDa). Finally, pairing pre- and postsynaptic activity elicited long-term potentiation in synapses between neurons expressing NR1 mRNA (P-to-AP synapse) and this potentiation was blocked by the NMDAR antagonist AP5.

Dendritic spikes as a mechanism for cooperative long-term potentiation.

Strengthening of synaptic connections following coincident pre- and postsynaptic activity was proposed by Hebb as a cellular mechanism for learning. Contemporary models assume that multiple synapses must act cooperatively to induce the postsynaptic activity required for hebbian synaptic plasticity. One mechanism for the implementation of this cooperation is action potential firing, which begins in the axon, but which can influence synaptic potentiation following active backpropagation into dendrites. Backpropagation is limited, however, and action potentials often fail to invade the most distal dendrites. Here we show that long-term potentiation of synapses on the distal dendrites of hippocampal CA1 pyramidal neurons does require cooperative synaptic inputs, but does not require axonal action potential firing and backpropagation. Rather, locally generated and spatially restricted regenerative potentials (dendritic spikes) contribute to the postsynaptic depolarization and calcium entry necessary to trigger potentiation of distal synapses. We find that this mechanism can also function at proximal synapses, suggesting that dendritic spikes participate generally in a form of synaptic potentiation that does not require postsynaptic action potential firing in the axon.

Atropine inhibits associative potentiation in the hippocampus.

The effects of the muscarinic receptor blocker atropine on associative long-term potentiation were studied in the CA1 region of the rat hippocampus. Focal excitatory post-synaptic potentials (EPSP) were recorded in living slices. Local application of atropine (0.1 mM) significantly inhibited associative long-term potentiation (40-60 min after tetanization) in the "weak" input (str. radiatum 128 +/- 10% compared with 168 +/- 9% in controls). Long-term potentiation at the "strong" input (str. oriens) was increased relative to the control (from 137 +/- 13% to 158 +/- 4%). These results indicate that endogenous acetylcholine aids the development of long-term potentiation in synapses with low levels of activation.

Increase in synaptic vesicle proteins accompanies long-term potentiation in the dentate gyrus

Maintenance of long-term potentiation in synapses formed by the perforant path on to granule cells of the dentate gyrus is accompanied by a sustained increase in the extracellular concentration of glutamate, 3,4 the presumed transmitter at this excitatory hippocampal pathway. Quantal analysis 2,12,13,19,27 indicates that, at least in the first hour of induction, this reflects an increase in transmitter release rather than a decrease in glutamate uptake, while biochemical studies 4,17,18 have suggested that the increase in release persists for several hours. Morphological studies have described early but persistent increases in the spine number 5,14 and area. 28 Increases in the number of segmented/perforated synapses persisting for at least 1 h after induction of long-term potentiation, have also been reported. 9,24 These morphological changes suggest both presynaptic and postsynaptic modifications. 15 Increases in synaptic vesicle number 20 and distribution 1 lasting for at least 1 h specifically indicate presynaptic changes. To explore further the role of the presynaptic terminal in long-term potentiation, we have investigated changes in three synaptic vesicle proteins, synapsin, synaptotagmin and synaptophysin, in control tissue and in tissue prepared from potentiated dentate gyrus 45 min and 3 h after induction of long-term potentiation. We found that there was an increase in the concentration of the three proteins 3 h after induction of long-term potentiation. No such increase was observed 45 min after induction or in tissue prepared from animals in which an intraventricular injection of the N-methyl- d-aspartate receptor antagonist, D(−)-2-amino-5-phosphonopentanoic acid, blocked induction of long-term potentiation. This finding demonstrates an increased expression of synaptic vesicle proteins in long-term potentiation and implies the existence of distinct temporal phases of long-term potentiation during which different synaptic mechanisms for increased transmitter release are engaged.

Transsynaptic expression of a presynaptic glutamate receptor during hippocampal long-term potentiation.

Repetitive activation of excitatory synapses in the hippocampus produces a persistent enhancement of synaptic efficiency known as long-term potentiation (LTP). In anesthetized and in freely moving rats, the induction of LTP in the perforant path led to a transient increase in the amount of messenger RNA (mRNA) coding for a presynaptic glutamate receptor (GR33) in dentate granule cells. The amount of GR33 mRNA was increased for at least 5 hours after the induction of LTP but was indistinguishable from control values 1 day after induction. The N-methyl-D-aspartate receptor antagonist 2-aminophosphonovalerate prevented the induction of both LTP and the increase in GR33 mRNA. The amount of GR33 protein was increased in the mossy fiber terminal zone of dentate granule cells 5 hours after the induction of LTP. These results suggest that the induction of LTP in synapses at one stage in a neural network may lead to modification in synaptic function at the next stage in the network.

Enhancement of transmitter release accompanying with long-term potentiation in synapses between mossy fibers and CA3 neurons in hippocampus

This study was performed to answer the question whether long-term potentiation (LTP) in mossy fiber-CA3 synapses is accompanied by an enhanced release of transmitter. For this purpose, the relative magnitude of amplitude fluctuation (coefficient of variation, CV) of excitatory postsynaptic potentials (EPSPs) and the probability of transmission failures were examined in thin hippocampal sections from the guinea pig before and after tetanic stimulation of mossy fibers or alteration of Ca 2+ concentration. The values of CV were reduced in association with increases in EPSP amplitude after tetanic stimulation or at high Ca 2+ concentration. The probability of failures decreased after tetanic stimulation. These findings indicate an enhancement of release of transmitter from mossy fiber terminals after induction of LTP.