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.     

The metabotropic glutamate receptor agonist 1S,3R-ACPD stimulates and modulates NMDA receptor mediated excitotoxicity in organotypic hippocampal slice cultures

The potential toxic effects of the metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) and its interactions with the N-methyl- -aspartate (NMDA) receptor were studied in hippocampal brain slice cultures, using densitometric measurements of the cellular uptake of propidium iodide (PI) to quantify neuronal degeneration. Cultures exposed to ACPD, showed a concentration (2–5 mM) and time (1–4 days) dependent increase in PI uptake in CA1, CA3 and dentate subfields after 24 h and 48 h of exposure, with CA1 pyramidal cells being most sensitive. The neurodegeneration induced by 2 mM ACPD was completely abolished by addition of 10 μM of the NMDA receptor antagonist (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), while 20 μM of the 2-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainic acid receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX) had no effect. Co-exposing cultures to a subtoxic dose of 300 μM ACPD together with 10 μM NMDA, which at this dose is known to induce a fairly selective degeneration of CA1 pyramidal cells, significantly increased the PI uptake in both CA1 and CA3, compared to cultures exposed to 10 μM NMDA only. Adding the 300 μM ACPD as pretreatment for 30 min followed by a 30 min wash in normal medium before the ACPD/NMDA co-exposure, eliminated the potentiation of NMDA toxicity. The potentiation was also blocked by addition of 10 or 100 μM 2-methyl-6-(phenylethynyl)pyridine (MPEP) (mGluR5 antagonist) during the co-exposure, while a corresponding addition of 10 or 100 μM 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) (mGluR1 antagonist) had no effect. We conclude that, stimulation of metabotropic glutamate receptors with ACPD at concentrations of 2 mM or higher induces a distinct subfield-related and time and concentration dependent pattern of hippocampal degeneration, and that ACPD at subtoxic concentrations modulates NMDA-induced excitotoxicity through the mGluR5 receptor in a time dependent way.     

NMDA receptor, protein kinase C and calmodulin system participate in the long-term potentiation in guinea pig superior colliculus slices

To investigate the involvement ofN-methyl-d-aspartate (NMDA) receptor, protein kinase C (PKC) and calmodulin on long-term potentiation (LTP) formation in the superior colliculus (SC), the effects of an NMDA receptor antagonist (d-APV), PKC inhibitors (H-7, K-252a, K-252b, polymyxin B), a protein kinase A (PKA) inhibitor (H-8) and a calcium/calmodulin-dependent kinase inhibitor (calmidazolium) on LTP formation were studied in guinea pig SC slices. APV (100 μM) masked the expression of LTP by tetanic stimulation, but the LTP once formed was not influenced by application of APV. LTP was blocked by application of H-7 (100 μM), but LTP reappeared 20 min after removal of H-7 from the perfusion medium without further tetanic stimulation. On the other hand, established LTP was also inhibited by application of H-7 even 90 min after the tetanic stimulation. Application of K-252a (500 nM) inhibited LTP formation, but K-252b (500 nM) had no inhibitory effect on LTP formation since K-252b, unlike K-252a, cannot permeate the cell membrane. Tetanic stimulation was applied 20 min after application of polymyxin B (1 μM) to the medium but it could not induce LTP, while established LTP was not influenced by the drug. Application of calmidazolium (50 μM) inhibited LTP formation, but had no inhibitory effect on LTP once formed. These results suggest that both the NMDA receptor and calmodulin system are involved in the induction of LTP after tetanic stimulation. This leads to PKC activation which maintains the LTP.     

Involvement of NMDA receptors and voltage-dependent calcium channels on augmentation of long-term potentiation in hippocampal CA1 area of morphine dependent rats

The involvement of NMDA receptors and voltage-dependent calcium channels on augmentation of long-term potentiation (LTP) was investigated at the Schaffer collateral–CA1 pyramidal cell synapses in hippocampal slices of morphine dependent rats, using primed-bursts tetanic stimulation. The amplitude of population spike was measured as an index of increase in postsynaptic excitability. d,l-AP5 and nifedipine were used as NMDA receptor antagonist and voltage-dependent calcium channel blocker, respectively. The amount of LTP of orthodromic population spike amplitude was higher in slices from dependent rats. Perfusion of slices from control or dependent rats with ACSF containing either d,l-AP5 (25 μM) or nifedipine (10 μM) and delivering tetanic stimulation, showed that d,l-AP5 completely blocked LTP of OPS in slices from both control and dependent rats, while nifedipine attenuated the amount of LTP of OPS in dependent slices and had no effect on control ones. The results suggest that the enhanced LTP of OPS in the CA1 area of hippocampal slices from morphine dependent rats is primarily induced by the NMDA receptors activity and the voltage-dependent calcium channels may also be partially involved in the phenomenon.     

Involvement of N-methyl-D-aspartate receptor subunits in zinc-mediated modification of CA1 long-term potentiation in the developing hippocampus

Zinc is an endogenous N-methyl-D-aspartate (NMDA) receptor blocker. It is possible that zinc-mediated modification of hippocampal CA1 long-term potentiation (LTP) is linked to the expression of NMDA receptor subunits, which varies with postnatal development. In the present study, the effect of ZnCl(2) and CaEDTA, a membrane-impermeable zinc chelator, on CA1 LTP induction was examined in hippocampal slices from immature (3-week-old) and young (6-week-old) rats. Tetanus (10-100 Hz, 1 sec)-induced CA1 LTP was more greatly enhanced in 3-week-old rats. CA1 LTP was inhibited in the presence of 2-amino-5-phosphonovalerate (APV), an NMDA receptor antagonist, and CaEDTA in 3-week-old rats, as in the case of 6-week-old rats reported previously. In 3-week-old rats, on the other hand, 5 μM ZnCl(2) attenuated NMDA receptor-mediated EPSPs more than in 6-week-old rats and significantly attenuated CA1 LTP. Moreover, 5 μM ZnCl(2) significantly attenuated CA1 LTP in the presence of (2R,4S)-4-(3-phosphonopropyl)-2-piperidinecarboxylic acid (PPPA), an NR2A antagonist, in 3-week-old rats, but not that in the presence of ifenprodil, an NR2B antagonist, suggesting that zinc-mediated attenuation of CA1 LTP is associated with the preferential expression of NR2B subunit in 3-week-old rats. In 6-week-old rats, however, 5 μM ZnCl(2) significantly potentiated CA1 LTP and also CA1 LTP in the presence of PPPA. The present study demonstrates that endogenous zinc may participate in the induction of CA1 LTP. It is likely that the changes in expression of NMDA receptor subunits are involved in the zinc-mediated modification of CA1 LTP in the developing hippocampus.     

Serotonin inhibits induction of long-term potentiation at commissural synapses in hippocampus

This study tests the effect of serotonin (5-HT) (1 μM) on the induction of long-term potentiation (LTP) at the commissural/associational (C/A)-CA3 synapse. The C/A input to CA3 was measured by field potentials in rat hippocampal slices. At the concentrations used 5-HT had little or no effect on synaptic transmission, but suppressed the induction of LTP. Similar results were observed in normal saline and in saline containing picrotoxin (10 μM) and bicuculline (10 μM) to block GABA_A inhibition. Perfusion with methylsergide (1 μM), a 5-HT antagonist, had no effect on synaptic transmission, but partially blocked the effect of 5-HT on LTP. The block of LTP by 5-HT could be overcome by using a higher intensity of stimulation suggesting that 5-HT might hyperpolarize the postsynaptic neurons to inhibit LTP induction. We conclude that the activation of serotonergic receptors inhibits the induction of LTP at the C/A-CA3 synapse.     

The effects of Zn on long-term potentiation of C fiber-evoked potentials in the rat spinal dorsal horn

Tetanic stimuli of peripheral C fibers produces long-term potentiation (LTP) in the spinal cord, which may contribute to sensitization of spinal pain-sensitive neurons. Zn²⁺ is widely distributed in the central nervous system and has blocked (LTP) in the hippocampus. The present study examined the effects of Zn²⁺ on the induction and maintenance of C fiber-evoked LTP in the deep dorsal horn of spinalized rats in vivo. The sciatic nerve was stimulated by tetanic stimuli for inducing LTP. (1) Topical administration of Zinc chloride (15 μM) to the spinal cord 15 min before tetanic stimulation completely blocked the induction of LTP, but not the baseline C responses. When Zn²⁺ was given 2 h after induction of LTP, no significant effect occurred. (2) Chelation of Zn²⁺ by disodium calcium ethylene diaminetelraacetate (CaEDTA) (500 μM) resulted in no effect on LTP. (3) Coadministration of Zn²⁺ (15 μM) and N-methyl-D-aspartic acid (NMDA) (5 μM) significantly attenuated C fiber-evoked potentials, which was prevented by the NMDA receptor antagonist AP-5 (100 μM). The present results showed that Zn²⁺ may contribute to the modulation of the formation, but not the maintenance, of spinal LTP. NMDA receptors may be involved in Zn²⁺-induced modulation.     

Delayed neuronal injury induced by sub-lethal NMDA exposure in the hippocampal slice

Stroke produces neuronal death by two general processes which differ in their temporal course. Acute neuronal death occurs within minutes, while delayed neuronal death evolves within 24 h. To better examine mechanisms of delayed death, we developed a new in vitro model of delayed neuronal injury using extended electrophysiological recordings in paired hippocampal slices. We exposed one hippocampal slice of each pair to 10 μMN-methyl-d-aspartate (NMDA) until the orthodromic CA1 PS disappeared. Thereafter, NMDA-treated slices regained near full recovery of PS amplitude within one hour. However, 10 h later, NMDA-treated slices demonstrated a rapid decline in PS amplitude of 82% ± 15. CA1 orthodromic evoked PS was lost completely at an average 12.4 ± 1.6 h after NMDA exposure. This sudden loss of response contrasted with paired, untreated slices, where CA1 PS could be elicited for 22.6 ± 4.0 h (P < 0.05). Treatment with 10 mM MgCl₂ begun after NMDA exposure and continued for 35 min, prevented delayed loss of CA1 orthodromic PS, which then could be elicited for 20.3 ± 2.1 h. These results indicate that delayed injury can be evaluated using the hippocampal slice. They also suggest that activation of NMDA receptors can induce delayed neuronal injury in CA1 neurons, and that magnesium treatment after NMDA can prevent this injury.     

Calcineurin inhibitors, FK506 and cyclosporin A, suppress the NMDA receptor-mediated potentials and LTP, but not depotentiation in the rat hippocampus

The effects of FK506, a Ca²⁺/calmodulin-dependent phosphatase 2B (calcineurin) inhibitor, on the NMDA receptor-mediated potentials and synaptic plasticity were investigated in the CA1 region of the rat hippocampus. Bath application of FK506 (50 μM) produced a 45% inhibition on the NMDA receptor-mediated potentials. FK506 also inhibited the induction of long-term potentiation (LTP), but had no effect on the depotentiation in the CA1 hippocampus. Cyclosporin A (100 μM), another calcineurin inhibitor, mimicked the effects of FK506 on the NMDA responses and synaptic plasticity. These results suggest that FK506 inhibits the activity of NMDA receptors via the involvement of calcineurin. The differential effects of FK506 on LTP and depotentiation may attribute to the partial inhibition on the activity of NMDA receptors and the subsequent attenuation of intracellular Ca²⁺ increase.     

N-Methyl-

In a whole-cell patch-clamp configuration, currents through N-methyl- -aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor channels were monitored in cultured rat hippocampal neurons, and those currents were depressed to 25 and 28% of basal levels, respectively, by 3-min treatment with tunicamycin (10 μM), an inhibitor of protein N-glycosylation. Tunicamycin (10 μM) reduced amplitude of population spikes elicited in the dentate gyrus of rat hippocampal slices, reaching 78% of basal levels 60 min after the beginning of treatment, and long-term potentiation (LTP) of the perforant path was never induced in the presence of tunicamycin. Tunicamycin, thus, appears to serve as a modulator for NMDA and AMPA receptors, regardless of N-glycosylation, thereby inhibiting neurotransmission and LTP in the dentate gyrus.     

Tunicamycin inhibits NMDA and AMPA receptor responses independently of N-glycosylation

In a whole-cell patch-clamp configuration, currents through N-methyl- -aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor channels were monitored in cultured rat hippocampal neurons, and those currents were depressed to 25 and 28% of basal levels, respectively, by 3-min treatment with tunicamycin (10 μM), an inhibitor of protein N-glycosylation. Tunicamycin (10 μM) reduced amplitude of population spikes elicited in the dentate gyrus of rat hippocampal slices, reaching 78% of basal levels 60 min after the beginning of treatment, and long-term potentiation (LTP) of the perforant path was never induced in the presence of tunicamycin. Tunicamycin, thus, appears to serve as a modulator for NMDA and AMPA receptors, regardless of N-glycosylation, thereby inhibiting neurotransmission and LTP in the dentate gyrus.     

Mu opioids enhance mossy fiber synaptic transmission indirectly by reducing GABAB receptor activation

The cellular mechanisms underlying mu opioid facilitation of mossy fiber (MF) long-term potentiation (LTP) and synaptic transmission were investigated in the rat hippocampal slice. Naloxone (10 μM) significantly inhibited the induction of mossy fiber LTP, an effect attributed by Derrick and Martinez [B.E. Derrick, J.L.J. Martinez, Opioid receptor activation is one factor underlying the frequency dependence of mossy fiber LTP induction, J. Neurosci. 14 (1994) 4359–4367] to antagonism of endogenous opioid peptide action. We found that the inhibitory effects of naloxone were not blocked by bicuculline, suggesting that endogenous opioids did not enhance mossy fiber LTP by depressing GABA_A inhibition. [ -Ala2, NMePhe4, Glyol5] enkephalin, DAMGO (300 nM), a mu opioid agonist, mimicked the action of endogenous opioids, enhancing both mossy fiber LTP induction and paired-pulse facilitation. DAMGO potentiation of the paired-pulse facilitation of mossy fiber response was also insensitive to bicuculline but was blocked by the mu selective antagonist CTOP. Further analysis of the cellular mechanism showed that the depletion of internal Ca²⁺ stores by thapsigargin (1 μM), or inhibition of protein kinases by application of staurosporine (1 μM) did not block the DAMGO facilitation of mossy fiber–CA3 synaptic transmission. However, application of phaclofen (100 μM GABA_B receptor antagonist or SCH 50911, a more potent GABA_B antagonist significantly inhibited the DAMGO effect (49±15%; 51±19% inhibition, P<0.05). The data indicate that the DAMGO effect on the mossy fiber pathway is partially mediated by a reduction in GABA activation of GABA_B receptors. These findings further suggest that endogenous opioid peptides activate mu opioid receptors to facilitate mossy fiber LTP and synaptic transmission in rat hippocampus partially by GABA_B receptor-mediated disinhibitory mechanism.     

Effects of a nitric oxide synthase inhibitor on NMDA receptor function in organotypic hippocampal cultures

Nitric oxide (NO) has been proposed to trigger long-term potentiation (LTP) at CA3 to CA1 synapses. We previously reported that NO synthesis inhibitors and blockers reduce an electrophysiological index of NMDA receptor activation in acute hippocampal slices. We now show that the NOS inhibitor, N^G-methyl-

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-arginine (MLA), also reversibly prevents LTP induction in organotypic hippocampal slices and significantly reduces a biochemical index of NMDA receptor function. These results further indicate that MLA inhibits LTP induction by interfering with NMDA receptor functions.     

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.     

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.     

Long-Term Potentiation in Hippocampal CA1: Effects of Afterdischarges, NMDA Antagonists, and Anticonvulsants

Long-term potentiation (LTP) of the basal dendritic population excitatory postsynaptic potential (EPSP) in hippocampal CA1 was readily elicited in behaving rats, without afterdischarges (ADs), by θ-frequency-patterned primed bursts (PBs) delivered to the contralateral CA1. A long-lasting postictal potentiation (PIP) was also elicited by high-frequency trains (1 s at 200 Hz), following an AD and a 5- to 10-min depression. The N -methyl- -aspartate (NMDA) antagonist 2-amino-phosphonovalerate was effective in blocking both LTP and PIP. The noncompetitive NMDA antagonist MK801 (0.5 mg/kg ip) attenuated the PB-induced LTP but enhanced PIP. The anticonvulsants phenytoin (40 mg/kg ip) and U54494A (25 or 50 mg/kg ip) had no effects on the LTP induced by a PB but they, like MK801, enhanced PIP to various degrees. The apparent enhancement of PIP by anticonvulsants may be a direct result of shortening the hippocampal AD duration and alleviation of the postictal EPSP depression. It is inferred that the typical hippocampal AD did not induce potentiation, but rather a postictal depression of the EPSP or a suppression of LTP. The mechanism of the postictal depression is likely different from the NMDA receptor-mediated LTP and PIP and it may depend on the AD duration (and perhaps excessive Ca²⁺ influx) but not critically on NMDA receptors.     

Inhibition of L-type voltage dependent calcium channels causes impairment of long-term potentiation in the hippocampal CA1 region in vivo

Long-term potentiation (LTP), in the hippocampal CA1 region is dependent on postsynaptic calcium influx. It is generally accepted that calcium influx occurs via activation of the NMDA receptor channel complex. However, studies in vitro using a high-frequency stimulus protocol (> or =200 Hz) demonstrated previously an NMDA receptor-independent form of LTP that is dependent upon activation of L-type voltage-dependent calcium channels (VDCCs). Here we have investigated a role for L-type VDCCs in LTP in vivo. Two structurally different, L-type VDCC blockers, verapamil (1, 3 and 10 mg/kg) and diltiazem (1, 10 and 20 mg/kg), depressed the induction of LTP in a dose-dependent manner. Increased activation of L-type VDCCs by Bay K 8644, an L-type agonist, however, did not enhance LTP. The NMDA receptor antagonist D-AP5 (5 and 20 mM injected i.c.v) impaired, but failed to block fully LTP in vivo. A reduced level of LTP could still be recorded following co-administration of verapamil and D-AP5. The level of LTP recorded was similar to that observed in the presence of either verapamil (10 mg/kg) or D-AP5 alone. These results suggest that activation of the NMDA receptor/channel and L-type VDCCs are involved in the induction of LTP in area CA1 in vivo. However, it appears that activation of other receptor/channels may also play a role in this form of LTP.     

N-methyl-D-aspartate receptor antagonists are less effective in blocking long-term potentiation at apical than basal dendrites in hippocampal CA1 of awake rats

Long-term potentiation (LTP) of field excitatory postsynaptic potentials (fEPSPs) at the apical or basal dendrites of CA1 pyramidal cells was induced by stimulation with a 1-s train of 200-Hz pulses in awake rats, with or without the presence of various doses of an N-methyl-D-aspartate (NMDA) receptor antagonist. Apical LTP was blocked by an intracerebroventricular (i.c.v.) dose of 40 microg D-2-amino-5-phosphonopentanoic acid (D-AP5) or 20 mg/kg i.p. D-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP-40116), whereas basal LTP was blocked by half the dose of D-AP5 or CGP-40116. The noncompetitive antagonist MK-801 (< or =1 mg/kg i.p.) had no significant effect on apical LTP. Apical LTP was not blocked by i.c.v. nifedipine. The effect of an NMDA receptor antagonist alone on apical and basal fEPSPs was also evaluated, to assess the net effect of the NMDA receptor antagonist in blocking LTP. MK-801 (0.5-1 mg/kg i.p.) or CGP-40116 (10-20 mg/kg i.p.) but not D-AP5 suppressed apical fEPSPs for several hours and confounded the expression of apical LTP during this time. We concluded that hippocampal LTP at different synapses has different sensitivity to NMDA receptor antagonists and that a general blockade of hippocampal NMDA receptor functions cannot be inferred by a single hippocampal LTP measure.     

Opioid receptors are involved in an NMDA receptor-independent mechanism of LTP induction at hippocampal mossy fiber-CA3 synapses.

Long-term potentiation (LTP) of mossy fiber responses in area CA3 of the rat hippocampus in vivo is blocked by naloxone, an opioid receptor antagonist, in a stereospecific and dose-dependent manner. LTP of commissural afferents to the same population of CA3 pyramidal cells is not attenuated by naloxone. This suggests that opioid receptors are involved in a mechanism of LTP induction that is specific to mossy fiber synapses, and that endogenous opioid receptors are involved in a mechanism of LTP induction that is specific to mossy fiber synapses, and that endogenous opioid peptides, presumably released as a result of mossy fiber stimulation, may be necessary for the induction of mossy fiber LTP. The naloxone sensitivity is limited to the induction phase of LTP, since naloxone does not reverse previously established LTP. These data suggest that LTP at the mossy fiber-CA3 synapse constitutes an NMDA receptor-independent, opioid receptor-dependent, form of hippocampal synaptic plasticity.