Differential Effect of TEA on Long-Term Synaptic Modification in Hippocampal CA1 and Dentate Gyrus in vitro

The effectiveness of tetraethylammonium (TEA) and high-frequency stimulation (HFS) in inducing long-term synaptic modification is compared in CA1 and dentate gyrus (DG) in vitro. High-frequency stimulation induces long-term potentiation (LTP) at synapses of both perforant path-DG granule cell and Schaffer collateral-CA1 pyramidal cell pathways. By contrast, TEA (25 mM) induces long-term depression in DG while inducing LTP in CA1. The mechanisms underlying the differential effect of TEA in CA1 and DG were investigated. It was observed that T-type voltage-dependent calcium channel (VDCC) blocker, Ni²⁺ (50 μM), partially blocked TEA-induced LTP in CA1. A complete blockade of the TEA-induced LTP occurred when Ni²⁺ was applied together with the NMDA receptor antagonist, D-APV. The L-type VDCC blocker, nifidipine (20 μM), had no effect on CA1 TEA-induced LTP. In DG of the same slice, TEA actually induced long-term depression (LTD) instead of LTP, an effect that was blocked by D-APV. Neither T-type nor L-type VDCC blockade could prevent this LTD. When the calcium concentration in the perfusion medium was increased, TEA induced a weak LTP in DG that was blocked by Ni²⁺. During exposure to TEA, the magnitude of field EPSPs was increased in both CA1 and DG, but the increase was substantially greater in CA1. Tetraethylammonium application also was associated with a large, late EPSP component in CA1 that persisted even after severing the connections between CA3 and CA1. All of the TEA effects in CA1, however, were dramatically reduced by Ni²⁺. The results of this study indicate that TEA indirectly acts via both T-type VDCCs and NMDA receptors in CA1 and, as a consequence, induces LTP. By contrast, TEA indirectly acts via only NMDA receptors in DG and results in LTD. The results raise the possibility of a major synaptic difference in the density and/or distribution of T-type VDCCs and NMDA receptors in CA1 and DG of the rat hippocampus.     

Enhanced proliferation of progenitor cells following long-term potentiation induction in the rat dentate gyrus

The dentate gyrus (DG) is among the few areas in the mammalian brain where production of new neurons continues in the adulthood. Although its functional significance is not completely understood, several lines of evidence suggest the role of DG neurogenesis in learning and memory. Considering that long-term potentiation (LTP) is a prime candidate for the process underlying hippocampal learning and memory, these results raise the possibility that LTP and neurogenesis are closely related. Here, we investigated whether or not LTP induction in the afferent pathway triggers enhanced proliferation of progenitor cells in the DG. LTP was induced by tetanic stimulation in perforant path-DG synapses in one hemisphere, and the number of newly generated progenitor (BrdU-labeled) cells in the DG was quantified. Compared with the control hemisphere (stimulated with low-frequency pulses), the LTP-induced hemisphere contained a significantly higher number of newly generated progenitor cells in the dorsal as well as ventral DG. When CPP, an NMDA receptor antagonist, was administered, tetanic stimulation neither induced LTP nor enhanced progenitor cell proliferation, indicating that NMDA receptor activation, rather than tetanic stimulation per se, is responsible for enhanced progenitor proliferation in the control animal. Our results show that tetanic stimulation of perforant path sufficient to induce LTP increases progenitor proliferation in adult DG in an NMDA receptor-dependent manner.     

Molecular mechanisms contributing to long-lasting synaptic plasticity at the temporoammonic-CA1 synapse

The hippocampus and the nearby medial temporal lobe structures are required for the formation, consolidation, and retrieval of episodic memories. Sensory information enters the hippocampus via two inputs from entorhinal cortex (EC): One input (perforant path) makes synapses on the dendrites of dentate granule cells as the first set of synapses in the trisynaptic circuit, the other (temporoammonic; TA) makes synapses on the distal dendrites of CA1 neurons. Here we demonstrate that TA-CA1 synapses undergo both early- and late-phase long-term potentiation (LTP) in rat hippocampal slices. LTP at TA-CA1 synapses requires both NMDA receptor and voltage-gated Ca2+ channel activity. Furthermore, TA-CA1 LTP is insensitive to the blockade of fast inhibitory transmission (GABAA-mediated) and, interestingly, is dependent on GABAB-dependent slow inhibitory transmission. These findings indicate that the TA-CA1 synapses may rely on a refined modulation of inhibition to exhibit LTP.     

The neural cell adhesion molecule-derived peptide FGL facilitates long-term plasticity in the dentate gyrus in vivo

The neural cell adhesion molecule (NCAM) is known to play a role in developmental and structural processes but also in synaptic plasticity and memory of the adult animal. Recently, FGL, a NCAM mimetic peptide that binds to the Fibroblast Growth Factor Receptor 1 (FGFR-1), has been shown to have a beneficial impact on normal memory functioning, as well as to rescue some pathological cognitive impairments. Whether its facilitating impact may be mediated through promoting neuronal plasticity is not known. The present study was therefore designed to test whether FGL modulates the induction and maintenance of synaptic plasticity in the dentate gyrus (DG) in vivo. For this, we first assessed the effect of the FGL peptide on synaptic functions at perforant path-dentate gyrus synapses in the anesthetized rat. FGL, or its control inactive peptide, was injected locally 60 min before applying high-frequency stimulation (HFS) to the medial perforant path. The results suggest that although FGL did not alter basal synaptic transmission, it facilitated both the induction and maintenance of LTP. Interestingly, FGL also modified the heterosynaptic plasticity observed at the neighboring lateral perforant path synapses. The second series of experiments, using FGL intracerebroventricular infusion in the awake animal, confirmed its facilitating effect on LTP for up to 24 h. Our data also suggest that FGL could alter neurogenesis associated with LTP. In sum, these results show for the first time that enhancing NCAM functions by mimicking its heterophilic interaction with FGFR facilitates hippocampal synaptic plasticity in the awake, freely moving animal.     

Induction and activity-dependent reversal of persistent LTP and LTD in lateral perforant path synapses in vivo

The reversibility of long-term potentiation (LTP) and heterosynaptic long-term depression (LTD) lasting weeks was examined in the lateral perforant path of freely moving adult Sprague-Dawley rats. LTP lasting weeks was rapidly reversed within minutes by high-frequency heterosynaptic stimulation of the medial perforant path, in an N-methyl-D-aspartate receptor-dependent manner. LTP reversal also occurred, albeit more slowly and to a lesser extent, when animals were given 1-3 weeks of overnight exposure to an enriched environment (EE). LTD likewise was reversed upon repeated EE exposure. A covert similarity between the degrees of LTP and LTD reversal was revealed when the small potentiation effect of EE treatment by itself on lateral path responses was taken into account. Despite its ability to reverse previously acquired synaptic plasticity, two weeks of EE treatment had no effect on animals' retention of the platform location in a spatial watermaze task, although it did facilitate new learning. These data are in agreement with the hypothesis that hippocampal synapses retain the capacity for rapid synaptic change even when otherwise relatively stable plasticity has previously been induced. Slow reversal of such plasticity did not correlate with a loss of memory retention, possibly because either slow changes permit reorganization of representations such that both old and new information can be accommodated, or else the new information is synaptically represented in orthogonal fashion to the old information.     

Alzheimer amyloid beta-peptide inhibits the late phase of long-term potentiation through calcineurin-dependent mechanisms in the hippocampal dentate gyrus

The perforant path projecting from the entorhinal cortex to the hippocampal dentate gyrus is a particularly vulnerable target to the early deposition of amyloid beta (Abeta) peptides in Alzheimer's brain. The authors previously showed that brief applications of Abeta at subneurotoxic concentrations suppressed the early-phase long-term potentiation (E-LTP) in rat dentate gyrus. The current study further examines the effect of Abeta on the late-phase LTP (L-LTP) in this area. Using multiple high-frequency stimulus trains, a stable L-LTP lasting for at least 3 h was induced in the medial perforant path of rat hippocampal slices. Bath application of Abeta(1-42) (0.2-1.0 microM) during the induction trains attenuated both the initial and late stages of L-LTP. On the other hand, Abeta(1-42) perfusion within the first hour following the induction primarily impaired the late stage of L-LTP, which resembled the action of the protein synthesis inhibitor emetine. Blockade of calcineurin activity with FK506 or cyclosporin A completely prevented Abeta-induced L-LTP deficits. These results suggest that Abeta(1-42) impaired both the induction and maintenance phase of dentate L-LTP through calcineurin-dependent mechanisms. In the concentration range effective for inhibiting L-LTP, Abeta(1-42) also reduced the amplitude of NMDA receptor-mediated synaptic currents in dentate granule cells via a postsynaptic mechanism. In addition, concurrent applications of Abeta(1-42) with the protein synthesis inhibitor caused no additive reduction of L-LTP, indicating a common mechanism underlying the action of both. Thus, inhibition of NMDA receptor channels and disruption of protein synthesis were two possible mechanisms contributing to Abeta-induced L-LTP impairment.     

A nitric oxide-independent and beta-adrenergic receptor-sensitive form of metaplasticity limits theta-frequency stimulation-induced LTP in the hippocampal CA1 region

The induction of long-term potentiation (LTP) and long-term depression (LTD) at excitatory synapses in the hippocampus can be strongly modulated by patterns of synaptic stimulation that otherwise have no direct effect on synaptic strength. Likewise, patterns of synaptic stimulation that induce LTP or LTD not only modify synaptic strength but can also induce lasting changes that regulate how synapses will respond to subsequent trains of stimulation. Collectively known as metaplasticity, these activity-dependent processes that regulate LTP and LTD induction allow the recent history of synaptic activity to influence the induction of activity-dependent changes in synaptic strength and may thus have an important role in information storage during memory formation. To explore the cellular and molecular mechanisms underlying metaplasticity, we investigated the role of metaplasticity in the induction of LTP by υ-frequency (5-Hz) synaptic stimulation in the hippocampal CA1 region. Our results show that brief trains of υ-frequency stimulation not only induce LTP but also activate a process that inhibits the induction of additional LTP at potentiated synapses. Unlike other forms of metaplasticity, the inhibition of LTP induction at potentiated synapses does not appear to arise from activity-dependent changes in NMDA receptor function, does not require nitric oxide signaling, and is strongly modulated by β-adrenergic receptor activation. Together with previous findings, our results indicate that mechanistically distinct forms of metaplasticity regulate LTP induction and suggest that one way modulatory transmitters may act to regulate synaptic plasticity is by modulating metaplasticity.     

Effects of reversible inactivation of locus coeruleus on long-term potentiation in perforant path-DG synapses in rats

The locus coeruleus (LC) is the main source of noradrenergic innervations to the forebrain and the hippocampal formation but does not receive noradrenergic projections itself. Previous studies have suggested that hippocampal neural response is modulated by the noradrenergic pathway and that the experimental activation of the LC can potentiate hippocampal responses. Most studies have suggested that the noradrenergic system has controversial effects on long-term potentiation (LTP) in hippocampal neurons, because its influence on synaptic plasticity in perforant path-DG synapses is ambiguous. The aim of this article was to study the LC's role in baseline activity and LTP in perforant path-DG cells of hippocampus by in vivo LC inactivation. Rats were anesthetized with urethane, and LC was temporarily suppressed by intra-LC injection of lidocaine. Population spike (PS) amplitude and excitatory postsynaptic potential (EPSP) slope in DG were recorded 10 min before and 5, 10, 20, 40, 60, and 120 min after tetanization (400 Hz). Saline or lidocaine was injected during the baseline recording (experiment 1), 5 min before tetanus (experiment 2), and 5 min after tetanus (experiment 3). The results from this study indicated that the LC inactivation has no effect on baseline activity of granular cells or maintenance of LTP after tetanization. Moreover, LC inactivation before tetanus had no effect on LTP induction but decreased PS-LTP amplitude 60 and 120 min after tetanization. Taken together, the LC noradrenergic system likely influences LTP induction in later time periods while it has no effect on LTP in earlier time periods.     

Differential effect of TEA on long-term synaptic modification in hippocampal CA1 and dentate gyrus in vitro.

The effectiveness of tetraethylammonium (TEA) and high-frequency stimulation (HFS) in inducing long-term synaptic modification is compared in CA1 and dentate gyrus (DG) in vitro. High-frequency stimulation induces long-term potentiation (LTP) at synapses of both perforant path-DG granule cell and Schaffer collateral-CA1 pyramidal cell pathways. By contrast, TEA (25 mM) induces long-term depression in DG while inducing LTP in CA1. The mechanisms underlying the differential effect of TEA in CA1 and DG were investigated. It was observed that T-type voltage-dependent calcium channel (VDCC) blocker, Ni2+ (50 microM), partially blocked TEA-induced LTP in CA1. A complete blockade of the TEA-induced LTP occurred when Ni2+ was applied together with the NMDA receptor antagonist, D-APV. The L-type VDCC blocker, nifidipine (20 microM), had no effect on CA1 TEA-induced LTP. In DG of the same slice, TEA actually induced long-term depression (LTD) instead of LTP, an effect that was blocked by D-APV. Neither T-type nor L-type VDCC blockade could prevent this LTD. When the calcium concentration in the perfusion medium was increased, TEA induced a weak LTP in DG that was blocked by Ni2+. During exposure to TEA, the magnitude of field EPSPs was increased in both CA1 and DG, but the increase was substantially greater in CA1. Tetraethylammonium application also was associated with a large, late EPSP component in CA1 that persisted even after severing the connections between CA3 and CA1. All of the TEA effects in CA1, however, were dramatically reduced by Ni2+. The results of this study indicate that TEA indirectly acts via both T-type VDCCs and NMDA receptors in CA1 and, as a consequence, induces LTP. By contrast, TEA indirectly acts via only NMDA receptors in DG and results in LTD. The results raise the possibility of a major synaptic difference in the density and/or distribution of T-type VDCCs and NMDA receptors in CA1 and DG of the rat hippocampus.     

Mutation at the TrkB PLC{gamma}-docking site affects hippocampal LTP and associative learning in conscious mice

Previous in vitro studies have characterized the electrophysiological properties and molecular events associated with long-term potentiation (LTP), but as yet there are no in vivo data from molecular-level dissection that directly identify LTP as the biological substrate for learning and memory. Understanding whether the molecular pathways required for learning are also those generating LTP when measured directly on the relevant circuit of a learning animal is clearly important, although so far has proved technically difficult. Here, for the first time, we combine highly defined genetic mouse models with behavior and in vivo recordings. We recorded the activity-dependent changes taking place at the CA3-CA1 synapses during the acquisition and extinction of a simple form of an associative learning task in mice carrying point mutations on specific docking sites of TrkB receptors (trkB(SHC), trkB(PLC)). The learning task consisted of a classical eyeblink conditioning using a trace paradigm. The conditioned stimulus (CS) consisted of a tone and was followed by a periorbital electrical shock as an unconditioned stimulus (US). The US started 500 msec after the end of the CS. We show that a single pulse presented to the Schaffer collateral-commissural pathway during the CS-US interval evoked a monosynaptic field excitatory postsynaptic potential (fEPSP) at the CA1 pyramidal cells, with a slope linearly related to learning evolution in controls and trkB(SHC) mutants, but the relationship was impaired in trkB(PLC) mice. These data support a link between the PLCgamma-docking site downstream of TrkB and the activity-dependent synaptic changes evoked at the CA3-CA1 synapses during associative learning in conscious mice, and indicate that TrkB PLCgamma-site-activated molecular pathway(s) underlie both associative learning and LTP triggered at the CA3-CA1 synapse.     

NT-3 facilitates hippocampal plasticity and learning and memory by regulating neurogenesis

In the adult brain, the expression of NT-3 is largely confined to the hippocampal dentate gyrus (DG), an area exhibiting significant neurogenesis. Using a conditional mutant line in which the NT-3 gene is deleted in the brain, we investigated the role of NT-3 in adult neurogenesis, hippocampal plasticity, and memory. Bromodeoxyuridine (BrdU)-labeling experiments demonstrated that differentiation, rather than proliferation, of the neuronal precursor cells (NPCs) was significantly impaired in DG lacking NT-3. Triple labeling for BrdU, the neuronal marker NeuN, and the glial marker GFAP indicated that NT-3 affects the number of newly differentiated neurons, but not glia, in DG. Field recordings revealed a selective impairment in long-term potentiation (LTP) in the lateral, but not medial perforant path-granule neuron synapses. In parallel, the NT-3 mutant mice exhibited deficits in spatial memory tasks. In addition to identifying a novel role for NT-3 in adult NPC differentiation in vivo, our study provides a potential link between neurogenesis, dentate LTP, and spatial memory.     

Dopamine transporter blockade increases LTP in the CA1 region of the rat hippocampus via activation of the D3 dopamine receptor

Dopamine has been demonstrated to be involved in the modulation of long-term potentiation (LTP) in the CA1 region of the hippocampus. As monoamine transporter blockade will increase the actions of endogenous monoamine neurotransmitters, the effect of a dopamine transporter (DAT) antagonist on LTP was assessed using field excitatory postsynaptic potentials recorded in the CA1 region of the rat hippocampal slice preparation. Application of the DAT-specific blocker GBR 12,935 produced a significant enhancement in LTP of Schaffer collateral synapses in the CA1 at concentrations as low as 100 nM. A selective D1/D5 dopamine receptor antagonist (SCH 23,390, 1 microM) did not affect the ability of GBR 12,935 to enhance LTP, whereas application of the D3 dopamine receptor antagonist U 99,194 (1 microM) blocked the GBR 12,935-induced enhancement in LTP. In addition, a D3 dopamine receptor agonist (7-OH-DPAT, 1 microM) caused a significant increase in LTP, an effect that was also blocked by U 99,194 (3 microM). These results suggest that either endogenously released dopamine (facilitated by DAT blockade) or exogenously applied dopamine agonist can act to increase LTP in the CA1 of the hippocampus via activation of the D3 subtype of dopamine receptor.     

A role for ERK MAP kinase in physiologic temporal integration in hippocampal area CA1

Recent studies demonstrate a requirement for the Extracellular signal Regulated Kinase (ERK) mitogen-activated protein kinase (MAPK) cascade in both the induction of long-lasting forms of hippocampal synaptic plasticity and in hippocampus-dependent associative and spatial learning. In the present studies, we investigated mechanisms by which ERK might contribute to synaptic plasticity at Schaffer collateral synapses in hippocampal slices. We found that long-term potentiation (LTP) induced with a pair of 100-Hz tetani does not require ERK activation in mice whereas it does in rats. However, in mice, inhibition of ERK activation blocked LTP induced by two LTP induction paradigms that mimicked the endogenous θ rhythm. In an additional series of studies, we found that mice specifically deficient in the ERK1 isoform of MAPK showed no impairments in tests of hippocampal physiology. To investigate ERK-dependent mechanisms operating during LTP-inducing stimulation paradigms, we monitored spike production in the cell body layer of the hippocampus during the period of θ-like LTP-inducing stimulation. θ-burst stimulation (TBS) produced a significant amount of postsynaptic spiking, and the likelihood of spike production increased progressively over the course of the three trains of TBS independent of any apparent increase in Excitatory Post-Synaptic Potential (EPSP) magnitude. Inhibition of ERK activation dampened this TBS-associated increase in spiking. These data indicate that, for specific patterns of stimulation, ERK may function in the regulation of neuronal excitability in hippocampal area CA1. Overall, our data indicate that the progressive increase in spiking observed during TBS represents a form of physiologic temporal integration that is dependent on ERK MAPK activity.     

Predator (cat hair)-induced enhancement of hippocampal long-term potentiation in rats: involvement of acetylcholine

Extensive literature has demonstrated that arousal and fear modify memory acquisition and consolidation. Predator hair and odors increase arousal in rats and, therefore, may influence information encoding and synaptic plasticity in the rodent nervous system. In behavioral experiments, we confirm that laboratory-bred Long Evans rats avoid cat hair. Electrophysiological work in vivo showed that long-term potentiation (LTP) in the dentate gyrus induced by perforant path stimulation was enhanced for 5-7 days when LTP induction occurred in the presence of cat hair relative to fake hair. The muscarinic receptor antagonist scopolamine (i.p.) reversed the cat hair-elicited LTP enhancement without affecting weaker LTP elicited in the presence of fake hair. Thus, exposure to a predator stimulus elicits a cholinergically-dependent state of heightened plasticity that may serve to facilitate information storage in hippocampal circuits.     

Limbic networks and associative learning: II. Entorhinal contributions to spontaneous alternation,passive avoidance,and taste aversion learning

The hippocampus plays an important role in learning and memory, but the precise nature of that involvement remains uncertain. Transection of the perforant path, a primary input pathway to the hippocampus, has been shown to produce changes in reaction to novelty and acquisition of active avoidance; the nature and magnitude of these changes vary with lateral or medial perforant path damage. In a series of experiments on adult rats, the role of these pathways in spontaneous alternation, exploration, acquisition and extinction of conditioned responses, passive avoidance, and conditioned taste aversion was investigated. Lateral transection reduced exploration while medial transection facilitated acquisition of an active avoidance response; no effects were observed on any other measure. Results are discussed in terms of what perforant path damage might reveal regarding the interactions of the hippocampus with other brain regions.     

海马CA_3区习得性LTP的进一步探讨

分辨学习中大鼠ＰＰ－ＣＡ_３突触效应有习得性ＬＴＰ产生,进一步观察到ＭＦ－ＣＡ_３及Ｃｏｍｍ－ＣＡ_３也同步地产生习得性ＬＴＰ,表明几种输入突触都产生习得性ＬＴＰ,而ＭＦ－ＣＡ_３突触效应增强的程度则较Ｃｏｍｍ－ＣＡ_３的为大（Ｐ＜０．０１）。海马ＣＡ_３注入印防己毒素能易化ＰＰ－ＣＡ_３突触习得性ＬＴＰ的产生,工作发现一侧海马ＣＡ_３注印防己毒素,易化对侧ＭＦ－ＣＡ_３突触习得性ＬＴＰ的产生,表明两侧海马ＣＡ_３区在其习得性ＬＴＰ的形成上是相互协同的。     

Limbic networks and associative learning: II. Entorhinal contributions to spontaneous alternation, passive avoidance, and taste aversion learning

The hippocampus plays an important role in learning and memory, but the precise nature of that involvement remains uncertain. Transection of the perforant path, a primary input pathway to the hippocampus, has been shown to produce changes in reaction to novelty and acquisition of active avoidance; the nature and magnitude of these changes vary with lateral or medial perforant path damage. In a series of experiments on adult rats, the role of these pathways in spontaneous alternation, exploration, acquisition and extinction of conditioned responses, passive avoidance, and conditioned taste aversion was investigated. Lateral transection reduced exploration while medial transection facilitated acquisition of an active avoidance response; no effects were observed on any other measure. Results are discussed in terms of what perforant path damage might reveal regarding the interactions of the hippocampus with other brain regions.