Long-term potentiation in the hippocampus involves activation of N-methyl-D-aspartate receptors

A series of ω-phosphono-α-car☐ylic acids were tested as antagonists of excitatory amino acid depolarizations and long-term potentiation (LTP) in region CA1 of rat hippocampal slices. The 5- and 7-phosphono compounds (±AP5and±AP7) blocked N-methyl-D-aspartate (NMDA) depolarizations and prevented the induction of LTP of the synaptic field potential and population spike components of the Schaffer collateral response.±AP5and±AP7 did not reduce kainate or quisqualate depolarizations and did not affect unpoten synaptic response amplitude.±AP5, ±AP6and±AP8 did not block amino acid excitant responses or LTP.These results demonstrate that NMDA receptors present in hippocampal region CA1 are not necessary for normal synaptic transmission, but are involved in the initiation of long-term synaptic plasticity.     

Induction of long-term potentiation in the basolateral amygdala does not depend on NMDA receptor activation.

Long-term potentiation (LTP) can be induced in the lateral and basolateral amygdala by stimulating synaptic afferents in the external capsule (EC). We examined the sensitivity of amygdaloid LTP to the NMDA receptor antagonist 2-amino-5-phosphonopentanoate (AP5), which is known to block LTP induction in the Schaffer collateral/CA1 synapses in the hippocampus. While relatively high concentrations (100 microM) of DL-AP5 were effective in preventing LTP induction in the lateral and basolateral amygdala in vitro, the same concentrations also significantly depressed synaptic responses to low-frequency stimulation. Furthermore, at 50 microM, a concentration sufficient to block both synaptic responses mediated by NMDA receptors and LTP induction in the hippocampus and neocortex, AP5 did not affect the probability of inducing LTP in the amygdala. Application of 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), which blocks non-NMDA excitatory amino acid receptors, reduced the monosynaptic response to EC stimulation by 85%. The remaining CNQX-insensitive response did not appear to be mediated by NMDA-type receptors, since it was not reduced by 50 or 100 microM AP5, and showed none of the voltage sensitivity characteristic of NMDA responses. These data suggest that while the induction of LTP in the amygdala produced by EC stimulation is blocked by high doses of AP5, plasticity at these synapses probably does not require activation of NMDA receptors.     

Prepubertal castration causes the age‐dependent changes in hippocampal long‐term potentiation

The effects of prepubertal castration on hippocampal CA3‐CA1 synaptic transmission and plasticity were studied at different ages in vitro. The field excitatory postsynaptic potentials (fEPSP) and population spikes (PS) were simultaneously recorded from stratum radiatum and stratum pylamidale of area CA1 following stimulation of Schaffer collaterals in slices taken from sham‐castrated and castrated rats at postnatal days (PND) 28, 35, 45, and 60. Castration had no effect on baseline responses at different ages except at PND 60 that a decrease in the fEPSP slope was seen. Prepubertal castration caused age‐specific changes in CA1‐long term potentiation (LTP) induction. The castration did decrease both fEPSP‐LTP and PS‐LTP at PND 35 but a decrease was seen only in PS‐LTP at PND 60. NMDA receptor antagonist AP5 (25 µM) completely blocked both fEPSP‐LTP and PS‐LTP at PND 60 and only PS‐LTP at PND 35 in both sham‐castrated and castrated groups. Although AP5 blocked fEPSP‐LTP at PND 35 in sham‐castrated group, it failed to inhibit fEPSP‐LTP at PND 35 in castrated one. These findings suggest that prepubertal castration causes the age‐dependent changes in CA1‐LTP induction, which might arise from alterations in the NMDA receptors. Synapse 67:235–244, 2013. © 2013 Wiley Periodicals, Inc.     

Reparatory effects of nicotine on NMDA receptor-mediated synaptic plasticity in the hippocampal CA1 region of chronically lead-exposed rats

Activation of neuronal nicotinic acetylcholine receptors (nAChRs) modulates the induction of long-term potentiation (LTP): a possible cellular mechanism of learning. To investigate the effect of nicotine on synaptic plasticity in chronically lead-exposed rats, field excitatory postsynaptic potentials and paired-pulse facilitation (PPF) were recorded in the CA1 area of hippocampal slices from chronically lead-exposed 23-30-day-old rats. The results showed the following. (1) Nicotine (1 microm) facilitated the induction of LTP in CA1 by a weak tetanic stimulation (100 Hz, 20 pulses), which does not by itself produce LTP in lead-exposed rats. This effect was significantly suppressed by mecamylamine, a nicotinic antagonist, suggesting that the facilitation of LTP was through nAChRs. (2) The nicotine-facilitated LTP was blocked by dihydro-beta-erythroidine (DHbetaE), a non-alpha7 nAChR antagonist, whereas long-term depression (LTD) was produced by the combination of nicotine and methyllycaconitine, a alpha7-nAChR antagonist. This type of LTD was blocked by DHbetaE. This suggested that several nAChR subtypes were involved in the nicotine-facilitated synaptic plasticity. (3) Nicotine enhanced PPF in the hippocampal CA1 region, and the nicotine-facilitated LTP in lead-exposed rats was blocked by either d-(-)-2-amino-5-phosphonopentanoic acid, the N-methyl-d-aspartate (NMDA) receptor antagonist, or picrotoxin, an antagonist of gamma-aminobutyric acid(A) receptors. We suggest that nicotine-facilitated synaptic plasticity was due to the activation of NMDARs by disinhibition of pyramidal cells through presynaptic nAChRs. This may represent the cellular basis of nicotine-facilitated cognitive enhancement observed in chronically lead-exposed rats.     

Pregnenolone sulfate enhances long-term potentiation in CA1 in rat hippocampus slices through the modulation of N-methyl-D-aspartate receptors

Among the different steroids found in the brain, pregnenolone sulfate (3beta-hydroxy-5-pregnen-20-one-3-sulfate; PREGS) is known to enhance hippocampal-associated memory. The present study employs rat hippocampal slices to investigate the ability of PREGS to modulate long-term potentiation (LTP), a phenomenon considered as a model of synaptic plasticity related to memory processes. LTP (3 x 100 Hz/1 sec within 2 min), implicated essentially glutamatergic transmission, for which the different synaptic events could be pharmacologically dissociated. We show that PREGS enhances LTP in CA1 pyramidal neurons at nanomolar concentrations and exhibits a bell-shaped concentration-response curve. The maximal effect of PREGS on both induction and maintenance phases of LTP is observed at 300 nM and requires 10 min of superfusion. Although PREGS does not change the N-methyl-D-aspartate (NMDA) component of the field potentials (fEPSPs) isolated in the presence of 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in Mg2+-free artificial cerebrospinal fluid, PREGS does enhance the response induced by NMDA application (50 microM, 20 sec). PREGS does not modify the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) component of the fEPSPs isolated in the presence of 100 microM DL-2-amino-7-phosphopentanoic acid (DL-AP5) or its potentiation induced by a single tetanic stimulation and the response induced by AMPA application (10 microM, 10 sec). Furthermore, PREGS does not affect the recurrent inhibition of the fEPSPs mediated by gamma-aminobutyric acid type A (GABA(A)) receptor. In conclusion, this study shows the ability of PREGS to enhance LTP in CA1 by accentuating the activity of NMDA receptors. This modulation of LTP might mediate the steroid-induced enhancement of memory.     

Role of N-methyl-D-aspartate receptors in the induction of synaptic potentiation by burst stimulation patterned after the hippocampal theta-rhythm

Short bursts of high frequency stimulation produce maximal long-term potentiation (LTP) at Schaffer-commissural synapses on CA1 neurons in hippocampal slices when the bursts are spaced 200 ms apart. A burst to one input (S1) does not induce LTP but 'primes' the postsynaptic neurons such that 200 ms later the postsynaptic response to a burst to a second input (S2) is greatly enhanced and LTP is induced. The role of N-methyl-D-aspartate (NMDA) receptors in this response enhancement and LTP induction was studied by perfusing slices with the NMDA antagonist, 2-amino-5-phosphonovalerate (AP5). AP5 (100 microM) had no effect on the field excitatory postsynaptic potential evoked by single pulse stimulation, but completely eliminated both the decremental short-term potentiation (lasting less than 10 min) and stable LTP effects elicited by burst stimulation. AP5 reduced the response to a non-primed burst by about 10% and reduced the relative enhancement of a primed burst response by about 35%. These results indicate that part of the postsynaptic response to a primed burst is mediated by NMDA receptors and that this component is necessary for all forms of synaptic potentiation (including LTP) resulting from burst stimulation. The similarity of the short bursts with the complex-spike discharges of hippocampal neurons as well as the 200 ms optimal interval with the period of the hippocampal theta-rhythm suggest links between theta and the NMDA receptor in the induction of hippocampal synaptic plasticity.     

Chemical LTD in the CA1 field of the hippocampus from young and mature rats

Within the hippocampal formation, two forms of long-lasting synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), can be induced which require the activation of NMDA receptors. Interestingly, it has been shown that both LTP and LTD are reduced in adult animals. Recently, a new chemical protocol has been described which elicits LTD in the CA1 field of the hippocampus. Application of 20 microM NMDA for 3 min results in a stable and long-lasting decrease in the evoked synaptic responses. We used this protocol to induce LTD in hippocampal slices from young and adult rats and show that this form of LTD is AP5-sensitive and can be blocked by the protein phosphatase inhibitor cyclosporin A in slices from adult animals. In contrast to electrical LTD (induced by prolonged low frequency stimulation), the extent of chemical LTD was not different between the young and adult rats. These findings indicate that the intracellular signal transduction cascades involved in long-lasting synaptic depression are still intact in adult animals.     

NMDA Receptor-dependent Transient Homo- and Heterosynaptic Depression in Picrotoxin-treated Hippocampal Slices

Extracellular recording was used to study the effects of high-frequency (tetanic) stimulation on excitatory synaptic transmission in the CA1 region of rat hippocampal slices in the presence of the _γ-aminobutyric acid (GABA) type A antagonist, picrotoxin (50 _γM). Under these conditions tetanic stimulation (100 Hz, 1 s) at the test intensity resulted in homosynaptic long-term potentiation (LTP). In contrast, tetanic stimulation of higher intensity (100 Hz, 1 s, double test intensity) resulted in homo- and heterosynaptic depression which recovered within 45 min. A transient (1–3 min) negative shift in DC potential and a transient (5–10 min) depression of the homosynaptic fibre volley occurred immediately following the higher intensity tetanus. The DC shift, induction of homo- and heterosynaptic depression and depression of the fibre volley were reversibly prevented by the N -methyl- d -aspartate (NMDA) receptor antagonist, d -2-amino-5-phosphonopentanoate (AP5; 20 _γM) but were not prevented by a variety of L-type calcium channel antagonists. Transient (30 - 45 min) synaptic depression of pharmacologically isolated NMDA receptor-mediated field excitatory postsynaptic potentials also occurred following tetanic stimulation (100 Hz, 1 s) at double test intensity. These results demonstrate an NMDA receptor-dependent form of reversible synaptic depression in the CA1 region of the hippocampus.     

NMDA receptor dependence of the input specific NMDA receptor-independent LTP in the hippocampal CA1 region

An important characteristic of long-term potentiation (LTP) in the hippocampal CA1 region is that it is specific for those synapses which are active during the induction event. This input specificity is commonly attributed to the location and properties of the N-methyl- -aspartate (NMDA) receptor channel. Experiments using strong high-frequency orthodromic activation have suggested that input-specific LTP can occur also in the absence of NMDA receptor activation. The present experiments have re-examined this question. They were performed in the CA1 region of hippocampal slices, and the synaptic strength was evaluated from the initial slope of the dendritically recorded field potential. In agreement with previous reports, 0.5 s. 200 Hz, orthodromic trains were found to lead to a substantial input-specific LTP (averaging 62%) in the presence of the competitive NMDA receptor antagonist -(−)-2-amino-5-phosphonopentanoic acid ( -AP5) (20 μM). Under conditions of higher NMDA receptor blockade considerably less LTP was evoked. In 50 μM -AP5 and 20 μM chloro-kynurenate LTP averaged 13.4%, and after addition of 20 μM (+)-dizicilpine malcate (MK-801) LTP averaged 5.9%. On the other hand, in 20 μM -AP5 and 20 μM of the calcium channel antagonist nifedipine LTP averaged 49.9%. The present results suggest that NMDA receptor activity remaining in high concentrations of AP5 is sufficient to underly LTP induction under strong induction conditions.     

Induction and expression of GluA1 (GluR-A)-independent LTP in the hippocampus

Long-term potentiation (LTP) at hippocampal CA3–CA1 synapses is thought to be mediated, at least in part, by an increase in the postsynaptic surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptors induced by N -methyl- d -aspartate (NMDA) receptor activation. While this process was originally attributed to the regulated synaptic insertion of GluA1 (GluR-A) subunit-containing AMPA receptors, recent evidence suggests that regulated synaptic trafficking of GluA2 subunits might also contribute to one or several phases of potentiation. However, it has so far been difficult to separate these two mechanisms experimentally. Here we used genetically modified mice lacking the GluA1 subunit ( Gria1 ^−/− mice) to investigate GluA1-independent mechanisms of LTP at CA3–CA1 synapses in transverse hippocampal slices. An extracellular, paired theta-burst stimulation paradigm induced a robust GluA1-independent form of LTP lacking the early, rapidly decaying component characteristic of LTP in wild-type mice. This GluA1-independent form of LTP was attenuated by inhibitors of neuronal nitric oxide synthase and protein kinase C (PKC), two enzymes known to regulate GluA2 surface expression. Furthermore, the induction of GluA1-independent potentiation required the activation of GluN2B (NR2B) subunit-containing NMDA receptors. Our findings support and extend the evidence that LTP at hippocampal CA3–CA1 synapses comprises a rapidly decaying, GluA1-dependent component and a more sustained, GluA1-independent component, induced and expressed via a separate mechanism involving GluN2B-containing NMDA receptors, neuronal nitric oxide synthase and PKC.     

Developmental Shift From Long-term Depression to Long-term Potentiation at the Mossy Fibre Synapses in the Rat Hippocampus

During development, in the CA1 hippocampal region, long-term potentiation (LTP) starts appearing at postnatal (P) day 7 and reaches its maximal expression towards the end of the second postnatal week. However, LTP is often preceded by long-term depression (LTD), an activity-dependent and long-lasting reduction of synaptic strength. LTD can be induced by sustained, low-frequency stimulation of the afferent pathway and is dependent on activation of N -methyl-D-aspartate (NMDA) receptors. We report here that, in the CA3 hippocampal region, during a critical period of postnatal development, between P6 and P14, a high-frequency stimulation train (100 Hz, 1 s) to the mossy fibres in the presence of the NMDA receptor antagonist (+)-3-(2-carboxy-piperazin-4-yl)-propyl-1-phosphonic acid (CPP; 20 μM) induced LTD. The depression of the amplitude of the field excitatory postsynaptic potential (EPSP) was 28 ± 7% ( n = 21). This form of LTD was NMDA-independent and synapse-specific. When a tetanus was applied in the presence of CPP and 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX; 50 μM), which blocked the field EPSP, it failed to induce LTD upon washout of CNQX. LTD was probably postsynaptic in origin since it did not affect paired-pulse facilitation. A rise in extracellular calcium concentration (from 2 to 4 mM) produced LTP instead of LTD. At the end of the second postnatal week, the same high-frequency stimulation train to the mossy fibres induced LTP as in adult neurons. Functional changes in synaptic connections during development may control membrane depolarization and the amount of intracellular calcium necessary to trigger either LTD or LTP.     

Effect of heparin‐binding growth‐associated molecule (HB‐GAM) on synaptic transmission and early LTP in rat hippocampal slices

Heparin-binding growth-associated molecule (HB-GAM) is an 18-kDa developmentally regulated protein, which promotes neurite outgrowth, axonal guidance and synaptogenesis through interaction with cell-surface heparan-sulphate proteoglycans. We have studied the effect of HB-GAM on synaptic transmission and long-term potentiation (LTP) in the area CA1 of rat hippocampal slices, where HB-GAM mRNA is expressed in an activity-dependent manner. Injection of recombinant HB-GAM into the dendritic area inhibited tetanus-induced LTP without affecting baseline synaptic responses or the N-methyl-d -aspartate (NMDA)-receptor mediated transmission. HB-GAM did not depotentiate tetanus-induced LTP or prevent heterosynaptic LTP induced by application of tetraethylammonium (TEA), indicating that the effect was limited to early, synapse-specific stages of LTP induction. These results suggest that HB-GAM is involved in the regulation of synaptic plasticity in hippocampus.     

Activation of NMDA receptors in hippocampal area CA1 by low and high frequency orthodromic stimulation and their contribution to induction of long-term potentiation

N-methyl-D-aspartate (NMDA) receptors are important in many instances of synaptic plasticity. In hippocampal area CA1, long-term potentiation (LTP) can be induced by both NMDA receptor-dependent and -independent mechanisms. Using intracellular recordings and single-electrode voltage clamp, we isolated and characterized NMDA receptor-mediated synaptic responses. NMDA receptor-mediated responses evoked by low frequency orthodromic stimulation were inhibited in a dose-dependent manner by the competitive antagonist D,L-2-amino-5-phosphonovaleric acid (APV). High frequency (tetanic) stimulation, which facilitates synaptic release of glutamate, failed to overcome the blockade of NMDA receptors by APV. Using extracellular recordings of field potentials, we studied the contribution of NMDA receptors to LTP induced by different patterns of tetanic stimulation. LTP was inhibited in a dose-dependent manner by APV, but was more sensitive to APV than were NMDA receptor-mediated synaptic responses. This most likely reflects a threshold for NMDA receptor activation in LTP induction. A component of LTP that resisted blockade by APV was induced by high (200 Hz), but not low (25 Hz), frequency tetanization. This NMDA receptor-independent component of LTP persisted for > 4 hours and accounted for approximately half the potentiation induced by 200 Hz tetanization. Procedures necessary to induce LTP at the Schaffer collateral/ commissural synapses in area CA1 by both NMDA receptor-dependent and -independent mechanisms are now well characterized. Using the same neuronal population, it will be possible to ask if processes involved in the maintenance of LTP are shared even when LTP is induced through two different mechanisms. © 1994 Wiley-Liss, Inc.     

Requirement of appropriate glutamate concentrations in the synaptic cleft for hippocampal LTP induction

Although glutamate transporters maintain low extracellular levels of the excitatory neurotransmitter glutamate in the nervous system, little is known about their roles in synaptic plasticity. Here, using knockout mice lacking GLT-1, that is the most abundant glial subtype of glutamate transporters, we showed that long-term potentiation (LTP) induced by tetanic stimulation in mutant mice was impaired in the hippocampal CA1 region. When tetanic stimulation was applied in the presence of low concentrations of an N-methyl-D-aspartate (NMDA) receptor antagonist, the impairment was overcome. Consistent with these results, the increased glutamate in the synaptic cleft of mutant mice preferentially activated NMDA receptors. Furthermore, analyses of mutant mice revealed that the magnitude of NMDA receptor-dependent transient synaptic potentiation during low-frequency stimulation depended on the concentration of glutamate in the synaptic cleft. These findings suggest that GLT-1 plays critical roles in LTP induction, as well as in short-term potentiation, through regulation of extracellular levels of glutamate, which enables appropriate NMDA receptor activation.     

Interferon-alpha inhibits long-term potentiation and unmasks a long-term depression in the rat hippocampus

Interferons (IFN) appear to have various neuromodulatory actions. Here, we characterized the actions of IFN-alpha on the electrophysiological properties of CA1 hippocampal neurons using intracellular recordings. Superfusion of this cytokine did not alter the resting membrane potential, cell input resistance, action potentials, nor GABA-mediated fast synaptic potentials. IFN-alpha inhibited glutamate-mediated excitatory postsynaptic potentials (gEPSPs) and reversed or prevented long-term potentiation (LTP) induced by high-frequency tetanic stimulation. IFN-alpha reduced gEPSP amplitude far below its control value. Only a short-term potentiation (STP) was observed when either IFN-alpha or D-2-amino-5-phosphonovalerato (APV; NMDA receptor antagonist) were present during tetanic stimulation. After this STP in presence of APV, IFN-alpha had no effect on gEPSPs. APV had no effect on LTP when applied after tetanic stimulation and did also not prevent IFN-alpha effect on LTP. Genistein (a tyrosine kinase inhibitor) or heat inactivation prevented IFN-alpha effects. IFN-alpha also decreased the depolarization induced by local application of glutamate but did not modify those induced by NMDA. Similarly, IFN-alpha reversed the potentiation (induced by tetanic stimulation) of glutamate-induced depolarizations. IFN-alpha did not affect long-term depression (LTD) induced by low-frequency tetanic stimulation. In conclusion, IFN-alpha-induced inhibition of LTP is, at least in part, mediated by a postsynaptic effect, by tyrosine kinase activity, and by non-NMDA glutamate receptors. Inhibition of LTP by IFN-alpha unmasks LTD which is induced by the same high-frequency tetanic stimulation.     

Activation of AP5-sensitive NMDA Receptors is Not Required to Induce LTP of Synaptic Transmission in the Lateral Perforant Path

The role of the N-methyl-d-aspartate (NMDA) type of glutamate receptor in long-term potentiation (LTP) of the medial (MPP) and lateral (LPP) divisions of the perforant path - granule cell system was investigated in urethane-anaesthetized rats. A stimulating electrode was positioned in the dorsomedial or ventrolateral aspect of the angular bundle for selective activation of either the MPP or LPP, respectively. A push - pull cannula served to focally perfuse artificial cerebrospinal fluid (ACSF) across the perforant path synaptic zone, while evoked potentials were monitored in the dentate hilus. Identification of LPP and MPP responses was based on (1) differences in population excitatory postsynaptic potential (EPSP) waveform obtained during stimulus depth profiles, and (2) differential sensitivity of evoked EPSPs to the glutamate receptor agonist l-aminophosphonobutyrate (AP4), and the antagonist gamma-d-glutamylglycine (DGG). High-frequency stimulation (400 Hz, 8 bursts of 8 pulses) applied to the lateral and medial perforant path elicited LTP of the EPSP and population spike in rats perfused with standard medium. In the MPP, LTP was almost completely blocked when d-aminophosphonopentanoate (AP5; 100 microM), a selective NMDA receptor antagonist, was perfused during the tetanus. Surprisingly, in the LPP experiments, AP5 did not impair induction of the 'synaptic' EPSP component of LTP. This occurred despite the ability of AP5 to block LTP of the LPP evoked population spike. The results suggest the existence of a novel, NMDA receptor-independent form of synaptic LTP in the lateral perforant path.     

Effects of TRPV1 on the hippocampal synaptic plasticity in the epileptic rat brain

Temporal lobe epilepsy is often presented by medically intractable recurrent seizures due to dysfunction of temporal lobe structures, mostly the temporomesial structures. The role of transient receptor potential vaniloid 1 (TRPV1) activity on synaptic plasticity of the epileptic brain tissues was investigated. We studied hippocampal TRPV1 protein content and distribution in the hippocampus of epileptic rats. Furthermore, the effects of pharmacologic modulation of TRPV1 receptors on field excitatory postsynaptic potentials have been analyzed after induction of long term potentiation (LTP) in the hippocampal CA1 and CA3 areas after 1 day (acute phase) and 3 months (chronic phase) of pilocarpine‐induced status epilepticus (SE). A higher expression of TRPV1 protein in the hippocampus as well as a higher distribution of this channel in CA1 and CA3 areas in both acute and chronic phases of pilocarpine‐induced SE was observed. Activation of TRPV1 using capsaicin (1 µM) enhanced LTP induction in CA1 region in non‐epileptic rats. Inhibition of TRPV1 by capsazepine (10 µM) did not affect LTP induction in non‐epileptic rats. In acute phase of SE, activation of TRPV1 enhanced LTP in both CA1 and CA3 areas but TRPV1 inhibition did not affect LTP. In chronic phase of SE, application of TRPV1 antagonist enhanced LTP induction in CA1 and CA3 regions but TRPV1 activation had no effect on LTP. These findings indicate that a higher expression of TRPV1 in epileptic conditions is accompanied by a functional impact on the synaptic plasticity in the hippocampus. This suggests TRPV1 as a potential target in treatment of seizure attacks. Synapse 69:375–383, 2015. © 2015 Wiley Periodicals, Inc.     

The Immediate Early Gene Arc Is Not Required for Hippocampal Long-Term Potentiation

Memory consolidation is thought to occur through protein synthesis-dependent synaptic plasticity mechanisms such as long-term potentiation (LTP). Dynamic changes in gene expression and epigenetic modifications underlie the maintenance of LTP. Similar mechanisms may mediate the storage of memory. Key plasticity genes, such as the immediate early gene Arc, are induced by learning and by LTP induction. Mice that lack Arc have severe deficits in memory consolidation, and Arc has been implicated in numerous other forms of synaptic plasticity, including long-term depression and cell-to-cell signaling. Here, we take a comprehensive approach to determine if Arc is necessary for hippocampal LTP in male and female mice. Using a variety of Arc knock-out (KO) lines, we found that germline Arc KO mice show no deficits in CA1 LTP induced by high-frequency stimulation and enhanced LTP induced by theta-burst stimulation. Temporally restricting the removal of Arc to adult animals and spatially restricting it to the CA1 using Arc conditional KO mice did not have an effect on any form of LTP. Similarly, acute application of Arc antisense oligodeoxynucleotides had no effect on hippocampal CA1 LTP. Finally, the maintenance of in vivo LTP in the dentate gyrus of Arc KO mice was normal. We conclude that Arc is not necessary for hippocampal LTP and may mediate memory consolidation through alternative mechanisms.SIGNIFICANCE STATEMENT The immediate early gene Arc is critical for maintenance of long-term memory. How Arc mediates this process remains unclear, but it has been proposed to sustain Hebbian synaptic potentiation, which is a key component of memory encoding. This form of plasticity is modeled experimentally by induction of LTP, which increases Arc mRNA and protein expression. However, mechanistic data implicates Arc in the endocytosis of AMPA-type glutamate receptors and the weakening of synapses. Here, we took a comprehensive approach to determine if Arc is necessary for hippocampal LTP. We find that Arc is not required for LTP maintenance and may regulate memory storage through alternative mechanisms.     

NMDA Receptor-dependent Long-term Potentiation in the Hippocampal Afferent Fibre System to the Prefrontal Cortex in the Rat

This study investigated the role of the N -methyl- d -aspartate (NMDA) subtype of glutamate receptor in the induction of long-term potentiation (LTP) in the hippocampal-prefrontal cortex pathway in vivo. Field potentials evoked by electrical stimulation of the CA1/subicular region were recorded in the prelimbic area of the prefrontal cortex under continuous perfusion of artificial cerebrospinal fluid in anaesthetized rats. High-frequency stimulation of the CA1/subicular region induced LTP of the evoked response in the prelimbic area of the prefrontal cortex. LTP was completely blocked when the selective NMDA receptor antagonist d -(-)2-amino-5- phosphonopentanoic acid ( d -AP5; 200 μM), was perfused during the tetanus. Perfusion of D-AP5 did not affect normal transmission or pre-established LTP. These results demonstrate that induction of LTP in the hippocampal-prefrontal cortex pathway is an NMDA receptor-dependent process.