Integrin alpha3beta1 suppresses long-term potentiation at inhibitory synapses on the cerebellar Purkinje neuron

At the GABAergic synapses between inhibitory interneurons and a Purkinje neuron (PN) in the cerebellum, the postsynaptic depolarization induces the long-term potentiation (called rebound potentiation; RP) of GABAA receptor responsiveness. Here, we show that integrins, a type of cell-adhesion molecules, are involved in the regulation of RP. Integrin activation by Mn2+ impaired the RP induction of GABA responsiveness and mIPSCs in PNs, which was abolished by the function blocking antibody against either integrin alpha3 or beta1 subunit, but not by that against alpha5 or alphaV subunit. Furthermore, overexpression of integrin alpha3 subunit in a PN by itself impaired the RP induction. We also show that Src-family of protein tyrosine kinases mediated the suppressive effect of integrin activity on the RP induction. Thus, the integrin/Src pathway negatively regulates the induction of long-term plasticity at inhibitory synapses on a cerebellar PN.     

Quisqualate Metabotropic Receptors Modulate NMDA Currents and Facilitate Induction of Long-Term Potentiation Through Protein Kinase C

Using intracellular and extracellular recordings in rat hippocampal slices, we have investigated the interactions between the quisqualate metabotropic receptor (Q_P) and currents mediated by N -methyl- d -aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). We found that trans- (t) -1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD) and 1S,3R-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) potentiated NMDA but not AMPA-mediated currents. Intracellular injections of selective protein kinase C inhibitors prevented the up-regulation of the NMDA response. The physiological consequence of the up-regulation by ACPD of the NMDA response on the threshold of long-term potentiation induction was tested. We found that a subthreshold train of electrical stimulation that produced short-term potentiation generated long-term potentiation when coupled with ACPD application, an effect which was not produced by AMPA or NMDA. This effect was blocked by an inhibitor of protein kinase C. These results demonstrate for the first time that one subtype of glutamate receptor (Q_P) can regulate another subtype of glutamate receptor (NMDA) through the activation of protein kinase C. Our results also suggest that the NMDA receptor is regulated by protein kinase C, and that the intracellular level of protein kinase C may determine the threshold for induction of long-term potentiation.     

Adenosine A1 receptor activation inhibits LTP in sympathetic ganglia

The effects of adenosine on long-term potentiation of sympathetic ganglia was studied in the isolated superior cervical ganglion of the rat, using extracellularly recorded compound action potential as an index of synaptic transmission. Adenosine in a small concentration (2 μM) blocked the post-tetanic potentiation without affecting long-term potentiation. Higher concentrations blocked both responses with no significant effect on basal transmission. The inhibitory effect appears to be due to activation of adenosine A1 receptors. This was indicated by results from experiments with the A1 agonist N⁶-cyclopentyladenosine (1 μM) which caused inhibition of the basal transmission as well as long-term potentiation and post-tetanic potentiation. This inhibition was readily antagonized by 8-phenyltheophylline (1 μM), an A1 receptor antagonist. A small enhancement of basal transmission was seen on treatment with 8-phenyltheophylline. The inhibitory effect of N⁶-cyclopentyladenosine on long-term potentiation was totally prevented when the Ca²⁺ concentration in the superfusate was doubled (from 2.2 to 4.4 mM). The adenosine A2 receptor agonist 5′-(N-cyclopropyl)-carboxamidoadenosine (1 μM), although caused a slight potentiation of basal transmission, had no significant effect on the post-tetanic potentiation or long-term potentiation. The adenosine transport inhibitors, dipyridamole (2 μM) and S-(4-nitorobenzyl)-6-thioinosine (2 μM) caused significant inhibition of the basal ganglionic transmission without affecting post-tetanic potentiation or long-term potentiation. The effect of dipyradimole on basal transmission was not antagonized in the presence of 8-phenyltheophylline suggesting a non-specific action. The results suggest that exogenous adenosine can inhibit both post-tetanic potentiation and long-term potentiation in sympathetic ganglia, probably by activation of presynaptic A1 receptors. The results also suggest that endogenous adenosine, which is probably released in minute amounts, may only modulate basal transmission without influencing induction or maintenance of long-term potentiation in the superior cervical ganglion.     

Change in bi-directional plasticity at CA1 synapses in hippocampal slices taken from 6-hydroxydopamine-treated rats: the role of endogenous norepinephrine

The object of the present study is to investigate the role of endogenous adrenergic innervation in regulating bi-directional synaptic plasticity in rat hippocampal CA1 synapses. The endogenous adrenergic system was eliminated by giving subcutaneous injection of 6-hydroxydopamine (6-OHDA) to rats immediately after birth, and the animals were killed for experiments at postnatal ages of 25-35 days. In hippocampal slices taken from 6-OHDA-treated animals, theta-burst stimulation at 100 Hz failed to induce long-term potentiation (LTP) at CA1 synapses. However, the induction of long-term depression (LTD) by prolonged low frequency stimulation at 1 Hz was unaffected in slices from 6-OHDA-treated animals. Bath application of norepinephrine (NE) restored LTP to control levels and blocked LTD. This effect was mimicked by beta- but not alpha-adrenergic receptor agonists, i.e. by isoproterenol but not phenylephrine. The activators of adenylyl cyclase and protein kinase A (PKA), i.e. forskolin and 8-bromoadenosine-3', 5'-cyclic monophosphate, respectively, restored LTP in slices from 6-OHDA-treated animals. In addition, application of the D1/D5 receptor agonist, dihydrexidine, also restored LTP in slices from 6-OHDA-treated animals. These results suggest that physiologically the recruitment of catecholamine innervation may be important for induction of LTP at hippocampal CA1 synapses during tetanic stimulation, while it may not be essential for LTD induction by prolonged 1 Hz stimulation. The released NE and dopamine exert their role in modulating synaptic plasticity via activation of beta-adrenergic and D1/D5 receptors, respectively, which in turn increase the levels of cytoplasm adenosine-3',5'-cyclic monophosphate and PKA.     

Modulation of protein kinases and protein phosphatases by reactive oxygen species: implications for hippocampal synaptic plasticity.

1. Reactive oxygen species are known for their role in neurotoxicity. However, recent studies indicate that reactive oxygen species also play a role in cell function under physiological conditions. 2. Both superoxide and hydrogen peroxide alter the activity of various protein kinases and protein phosphatases, some of which are involved in hippocampal synaptic plasticity. Specifically, the activity of protein kinase C, extracellular-regulated kinase 2, and a protein tyrosine kinase(s) is increased in the presence of these reactive oxygen species, whereas the activity of protein phosphatases 2A and 2B, and a protein tyrosine phosphatase(s) is decreased. 3. Protein kinase C, extracellular-regulated kinase 2, and protein tyrosine kinases critically participate in the induction and/or early expression of long-term potentiation at glutamatergic synapses in hippocampus. Protein phosphatases 2A and 2B participate in the induction and/or early expression of long-term depression at these synapses. 4. Treatment of hippocampal slices with scavengers of either superoxide or hydrogen peroxide prevents the full expression of long-term potentiation. Long-term potentiation in hippocampus also is attenuated in transgenic mice that overexpress Cu/Zn superoxide dismutase. 5. The link between reactive oxygen species and long-term potentiation may be the activating effect on protein kinases. The inhibiting effect of reactive oxygen species on protein phosphatases may also contribute to long-term potentiation. 6. The authors hypothesize that reactive oxygen species play a critical role in hippocampal long-term potentiation by favoring the activation of a protein kinase over a protein phosphatase signaling cascade.     

Antibodies to Postsynaptic PKC Substrate Neurogranin Prevent Long-term Potentiation in Hippocampal CA1 Neurons

Both pre- and postsynaptic protein kinase C have been implicated in long-term potentiation. Neurogranin (also known as BICKs and RC3) is a neuronal postsynaptic protein kinase C substrate. In the present study we injected monoclonal IgGs that recognize the protein kinase C phosphorylation site in neurogranin and B-50 (GAP-43), and that have been shown to inhibit protein kinase C-mediated B-50 phosphorylation, through a whole-cell clamp pipette into CA1 pyramidal neurons in rat hippocampal slices. Injection of neurogranin IgGs, but not of control IgGs, prevented the induction of tetanus-induced long-term potentiation without affecting posttetanic potentiation. Our results suggest that neurogranin is involved in mechanisms of activity-dependent synaptic plasticity.     

NMDA receptor regulation by amyloid-beta does not account for its inhibition of LTP in rat hippocampus

Accumulation of amyloid-beta peptide (Abeta) is widely believed to play a critical role in the pathogenesis of Alzheimer's disease. Although amyloid-containing plaques are a key neuropathological feature of AD, soluble forms of Abeta can interfere with synaptic plasticity in the brain, suggesting that this form of the peptide may be responsible for much of the memory deficit seen early in the disease. Here, we investigate the mechanism underlying the effects of Abeta on long-term potentiation (LTP) in area CA1 of rat hippocampus. Extracellular field recordings were made in area CA1 of hippocampal slices taken from young, adult male rats. A non-toxic concentration of Abeta (200 nM) produced a rapid inhibition of LTP induced by 100 Hz stimulation while having no long-term effect on normal synaptic transmission. The same dose of Abeta had no effect on long-term depression (LTD) induced by 1200 pulses at 1 or 3 Hz. Picrotoxin had no effect on the inhibition of LTP, suggesting Abeta does not act by enhancing GABAergic transmission. Since the LTP induction in this study was dependent on N-methyl-D-aspartate (NMDA) receptor activation, we looked at the effect of Abeta on isolated NMDA receptor-mediated field potentials. Abeta produced a small but significant inhibition of NMDA receptor-mediated synaptic potentials ( approximately 25%). However, a low dose of MK-801 (0.5 microM) that produced a similar inhibition of NMDA potentials had no effect on LTP induction but completely blocked LTD induction. These results suggest that Abeta does not inhibit LTP via effects on NMDA receptors, but rather interferes with a downstream pathway.     

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.     

Primed-burst potentiation occludes the potentiation phenomenon and enhances the epileptiform activity induced by transient pentylenetetrazol in the CA1 region of rat hippocampal slices

The effects of pentylenetetrazol (PTZ) following induction of long-term potentiation (LTP) on population spikes in CA1 of hippocampal slices were investigated. Population spikes were evoked by activation of Schaffer collaterals with a range of stimulation intensities. LTP was induced using θ-pattern primed burst tetanic stimulation. Changes in the population spike amplitude and number of population spikes were used as indices to quantify the effects of PTZ exposure in the control (non-tetanized) and LTP (tetanized) conditions. The amplitude of population spike was measured 20 min before, during 20 min chemical application (3 mM), and also after 30 or 60 min washout period. In non-tetanized slices, the population spike input-output curve was significantly increased 20 min after PTZ application and persisted at least for 60 min. Multiple population spikes or after potentials also appeared, but did not persist. When PTZ was applied on tetanized slices, 60 min after LTP induction, the amplitude increase produced by PTZ was smaller than the increase seen in the control condition. Also LTP induction preceding PTZ exposure increased the number of population spikes evoked by stimulation of Schaffer collaterals. It is concluded that a transient PTZ application produces a long-lasting increase in population spike amplitude. Primed burst LTP occludes PTZ-induced potentiation while also increasing the epileptogenic effect of PTZ.     

Lithium attenuates stress-induced impairment of long-term potentiation induction

Stress impairs the induction of long-term potentiation in the hippocampus as well as hippocampus-dependent memory. Lithium, a classical mood stabilizer, is known to have beneficial effects on stress-induced impairment of spatial memory. In the present study, we investigated lithium effects on the impairment of long-term potentiation induction after exposure to acute immobilization stress. As previously reported, immobilization stress impaired long-term potentiation induction in the CA1 region of rat hippocampal slices. Treating the slices with 0.6 or 1 mM lithium attenuated impaired long-term potentiation induction in stressed animals. Lithium was without effect on long-term potentiation induction in unstressed animals or baseline synaptic responses in unstressed or stressed animals. These results demonstrate a protective effect of lithium against stress-induced impairment of long-term potentiation induction.     

Adenosine antagonists have differential effects on induction of long-term potentiation in hippocampal slices

How adenosine leakage and tetanic release might affect long-term potentiation (LTP) was investigated by applying adenosine antagonists 8(p-sulfophenyl)theophylline (8SPT) or 8-cyclopentyl-3, 7-dihydro-1, 3-dipropyl-1H-purine-2, 6-dione (DPCPX) to slices, while recording CA1 field EPSPs and population spikes. In the first series of experiments, we applied weak double tetani (at 100 Hz, for 1 s) that were subliminal for evoking LTP in initial control runs. In the presence of 8SPT—at concentrations (10–50 μM) which block both A₁ and A₂ receptors—the same tetani consistently evoked LTP of population spikes but not of excitatory postsynaptic potentials (EPSPs), whereas DPCPX (50 nM), which blocks only A₁ receptors, facilitated LTP of both EPSPs and population spikes. These results are consistent with previous evidence that tetanic adenosine release on the one hand depresses LTP via A₁ receptors but on the other facilitates LTP via A₂ receptors. In a second set of experiments, 8SPT (50–100 μM) did not prevent the induction of LTP of both EPSPs and population spikes by stronger tetanic stimulation. Therefore A₂ receptor activation is not essential for the induction of LTP when stronger tetani are applied. Overall, the main effect of endogenous adenosine release is to oppose LTP induction. © 1995 Wiley-Liss, Inc.     

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.     

Prior short-term synaptic disinhibition facilitates long-term potentiation and suppresses long-term depression at CA1 hippocampal synapses

Long-term potentiation (LTP) and long-term depression (LTD) are two main forms of activity-dependent synaptic plasticity that have been extensively studied as the putative mechanisms underlying learning and memory. Current studies have demonstrated that prior synaptic activity can influence the subsequent induction of LTP and LTD at Schaffer collateral-CA1 synapses. Here, we show that prior short-term synaptic disinhibition induced by type A gamma-aminobutyric acid (GABA) receptor antagonist picrotoxin exhibited a facilitation of LTP induction and an inhibition of LTD induction. This effect lasted between 10 and 30 min after washout of picrotoxin and was specifically inhibited by the L-type voltage-operated Ca2+ channel (VOCC) blocker nimodipine, but not by the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphopentanoic acid (D-APV). Moreover, this picrotoxin-induced priming effect was mimicked by forskolin, an activator of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), and was blocked by the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22536) and the PKA inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate (Rp-cAMPS). It was also found that following picrotoxin application, CA1 neurons have a higher probability of synchronous discharge in response to a population of excitatory postsynaptic potential (EPSP) of fixed slope (EPSP/spike potentiation). However, picrotoxin treatment did not significantly affect paired-pulse facilitation (PPF). These findings suggest that a brief of GABAergic disinhibition can act as a priming stimulus for the subsequent induction of LTP and LTD at Schaffer collateral-CA1 synapses. The increase in Ca2+ influx through L-type VOCCs in turn triggering a cAMP/PKA signalling pathway is a possible molecular mechanism underlying this priming effect.     

The involvement of glia in long-term plasticity in the spinal dorsal horn of the rat

We have examined the potential role of spinal glial cells in the induction of C fiber-evoked long-term potentiation (LTP) in the spinal cord. Tetanic stimulation of the sciatic nerve induced longterm potentiation of C-fiber-evoked field potentials in the spinal dorsal horn in all rats. Following intrathecal fluorocitrate (1 nmol), a glial metabolic inhibitor, tetanic stimulation induced longterm depression (LTD) but not LTP. The effects of fluorocitrate were abolished by kynurenic acid or 2-amino-5-phosphonovaleric acid (AP-5), but not by 6,7-dinitroquinoxaline-2,3-dione (DNQX), picrotoxin or strychnine. These data suggest that spinal glial cells may modulate the central sensitization of nociceptive neurons via NMDA receptors.     

Potentiation of 3-hydroxyglutarate neurotoxicity following induction of astrocytic iNOS in neonatal rat hippocampal cultures

Neuronal damage in glutaryl-CoA dehydrogenase deficiency (GDD) has previously been addressed to N-methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity of the accumulating neurotoxic metabolite 3-hydroxyglutarate. However, acute encephalopathic crises in GDD patients are typically precipitated by febrile illness or even routine vaccinations, suggesting a potentiating role of inflammatory cytokines. In the present study we investigated the effect of interleukin-1beta and interferon-gamma on 3-hydroxyglutarate toxicity in rat cortical astrocyte cultures and neonatal rat hippocampal cultures. A cotreatment of both culture systems with interleukin-1beta and interferon-gamma induced the protein expression of astrocytic inducible nitric oxide synthase (iNOS), resulting in increased nitric oxide (NO) production. Cytokine pretreatment alone had no effect on cell viability but potentiated 3-hydroxyglutarate neurotoxicity. NOS inhibition by aminoguanidine and L-NAME prevented an iNOS-mediated potentiation of 3-hydroxyglutarate neurotoxicity but failed to protect neurons against 3-hydroxyglutarate alone. In contrast, superoxide dismutase/catalase as well as MK-801 prevented toxicity of 3-hydroxyglutarate alone as well as its potentiation by iNOS, supporting a central role of NMDA receptor stimulation with subsequently increased superoxide anion production. It is concluded that the potentiation of 3-hydroxyglutarate neurotoxicity is most probably due to an induction of astrocytic iNOS and concomitantly increased NO production, enabling enhanced peroxynitrite formation. Thus, we provide evidence for a neuroimmunological approach to the precipitation of acute encephalopathic crises in GDD by inflammatory cytokines.     

Evidence that matrix recognition contributes to stabilization but not induction of LTP

Slices of hippocampus were incubated with Arg-Gly-Asp (RGD) peptides known to block members of the integrin class of matrix receptors. Though the peptides caused no detectable difference in the amount of long-term potentiation (LTP) expressed in the CA1 field 1-2 min after induction with high frequency stimulation, they did produce a reversible, dose dependent decay of LTP over a period of 40 min. This effect was not obtained with various non-RGD control peptides. These results suggest that stabilization of LTP requires adhesive interactions via specific matrix recognition sites, whereas induction and expression do not.     

Fluvoxamine suppresses the long-term potentiation in the hippocampal CA1 field of anesthetized rats: an effect mediated via 5-HT1A receptors

A selective 5-HT reuptake inhibitor, fluvoxamine (10 and 30 mg/kg, i.p.) suppressed long-term potentiation (LTP) in the hippocampal CA1 field of anesthetized rats. Fluvoxamine (30 mg/kg, i.p.)-induced suppression of LTP was completely reversed by the 5-HT(1A) receptor antagonist NAN-190 (0.5 mg/kg, i.p), but not by the 5-HT(4) receptor antagonist GR 113808 (20 microg/rat, i.c.v.) and the 5-HT(7) receptor antagonist DR 4004 (10 microg/rat, i.c.v.). These data suggest that the inhibitory effect of fluvoxamine on LTP induction is mediated via 5-HT(1A) receptors.     

Factors regulating the magnitude of long-term potentiation induced by theta pattern stimulation

Electrical stimulation patterned after the hippocampal theta rhythm produces a robust and stable long-term potentiation (LTP) effect. Pharmacological manipulations were used in the present studies in an effort to relate characteristics of the responses occurring during theta stimulation to the magnitude of potentiation which follows it. Comparisons were made using five or ten bursts of stimulation which respectively induce sub-maximal or near maximal degrees of LTP. DPCPX, a drug that increases release by blocking adenosine A1 receptors, was used to enhance the depolarization produced by individual theta bursts. This resulted in a marked increase in the amount of stable LTP induced by five theta bursts but did not affect that resulting from ten bursts. This finding suggested that depolarization occurring during a burst response influences per burst potentiation but not the ceiling on maximum LTP. Aniracetam, a nootropic drug that enhances responses via an action on glutamate (AMPA) receptors, was used to test this conclusion. Like DPCPX, aniracetam increased the size of the burst response and enhanced the degree of LTP caused by five but not ten theta bursts. Forskolin, an activator of adenylate cyclase, was used to test the effects of blocking the hyperpolarization normally present between theta bursts on the induction of LTP. The drug augmented the degree of LTP resulting from five theta bursts and, in contrast to DPCPX and aniracetam, nearly doubled that obtained with ten bursts. Thus the drug affected both per burst potentiation and the ceiling on LTP. These results are discussed in terms of an hypothesis in which the magnitude of NMDA receptor mediated currents affects the degree of potentiation produced by individual theta bursts while the duration of the currents is related to the limit on the maximum LTP induced by a series of bursts. The possible implications of the findings for learning are also considered.     

Effect of bromophenacyl bromide, a phospholipase A2 inhibitor, on the induction and maintenance of LTP in hippocampal slices

The effect of bromophenacyl bromide (BPB), a phospholipase A₂ (PLA₂) inhibitor, on both the induction and the maintenance of long-term potentiation (LTP) was investigated in field CA₁ of the hippocampal slice preparation. One hour of BPB application (50 μM) caused a large reduction in the magnitude of LTP induced by a theta burst stimulation (TBS) paradigm. BPB had no significant effect on either the degree of paired-pulse facilitation or the amount of pre-established LTP. Furthermore, the facilitation of postsynaptic responses occuring during TBS and in the first minute following TBS was not reduced by the PLA₂ inhibitor. These results indicate that the inhibition of LTP produced by BPB is not due to an effect of the drug on a physiological event that triggers LTP. The data also suggest that PLA₂ activation plays a critical role in the expression of LTP, but is not required for the maintenance of the potentiation.     

Melatonin inhibits hippocampal long-term potentiation

The goal of this study is to investigate the effect of the hormone melatonin on long-term potentiation and excitability measured by stimulating the Schaffer collaterals and recording the field excitatory postsynaptic potential from the CA1 dendritic layer in hippocampal brain slices from mice. Application of melatonin produced a concentration-dependent inhibition of the induction of long-term potentiation, with a concentration of 100 nm producing an approximately 50% inhibition of long-term potentiation magnitude. Long-duration melatonin treatments of 6 h were also effective at reducing the magnitude of long-term potentiation. Melatonin (100 nm) did not alter baseline evoked responses or paired-pulse facilitation recorded at this synapse. The inhibitory actions of melatonin were prevented by application of the melatonin (MT) receptor antagonist luzindole as well as the MT2 receptor subtype antagonist 4-phenyl-2-propionamidotetraline. These inhibitory actions of melatonin were lost in mice deficient in MT2 receptors but not those deficient in MT1 receptors. In addition, application of the protein kinase A inhibitor H-89 both mimicked the effects of melatonin and precluded further inhibition by melatonin. Finally, the application an activator of adenylyl cyclase, forskolin, overcame the inhibitory effects of melatonin on LTP without affecting the induction of long-term potentiation on its own. These results suggest that hippocampal synaptic plasticity may be constrained by melatonin through a mechanism involving MT2-receptor-mediated regulation of the adenylyl cyclase-protein kinase A pathway.