Depotentiation of vdccLTP requires NMDAR activation.

Long-term potentiation is an enduring increase in synaptic efficacy following repeated stimulation of afferent fibers that is thought to underlie memory. In area CA1 of the hippocampus at least two forms of synaptic potentiation coexist at the same synapses; nmdaLTP and vdccLTP. NmdaLTP is induced by Ca2+ entry through NMDARs and is dependent on serine/threonine kinase activation, while vdccLTP is induced through Ca2+ entry through VDCCs and is dependent on tyrosine kinase activation. Depotentiation is a mechanism known to reverse nmdaLTP through phosphatase activation. The depotentiation of vdccLTP has not been previously investigated. We used hippocampal slices (area CA1) from male Long-Evans rats to induce vdccLTP with a 200-Hz tetanus in the presence of 50 microM APV. The 200-Hz tetanus resulted in a slowly developing vdccLTP that remained stable for at least 30 min. Thirty minutes after vdccLTP was induced, a low-frequency tetanus (3, 10, 20, 30, or 40 Hz) was applied in the presence of APV in an attempt to depotentiate vdccLTP. The 3- and 10-Hz low-frequency tetani resulted in no depotentiation. The 20- and 30-Hz tetani partially depotentiated vdccLTP (by approximately 13%), whereas the 40-Hz tetanus resulted in further potentiation. When APV was washed out prior to the 3-Hz low-frequency tetanus, the vdccLTP was completely depotentiated--presumably by NMDAR mechanisms. Our results indicate that vdccLTP is resistant to depotentiation under low-frequency stimulation conditions that readily depotentiate nmdaLTP. As tetanus frequencies are increased a small depotentiation is observed, suggesting that vdccLTP can be depotentiated to a small extent. When NMDARs are unblocked, vdccLTP can be completely depotentiated by a 3-Hz low-frequency tetanus, suggesting that vdccLTP can be depotentiated via activation of NMDAR mechanisms.

Tyrosine phosphorylation-dependent inhibition of hippocampal synaptic plasticity.

We examined the effects of two protein tyrosine phosphatase inhibitors on the induction of synaptic plasticity in CA1 slices of rat hippocampus. Field potential recordings were made in stratum radiatum in response to stimulation of the Schaffer collateral afferents. Bath application of the tyrosine phosphatase inhibitors sodium orthovanadate or phenylarsine oxide for 30 min had little effect on basal synaptic transmission but blocked the induction of both long-term potentiation (LTP) and homosynaptic long-term depression (LTD). LTP could be partially recovered, and LTD fully recovered, when conditioning stimulation was given in conditions of reduced synaptic inhibition. The block of both forms of synaptic plasticity by the phosphatase inhibitors correlated with a concurrent depression of the N-methyl-D-aspartate (NMDA) receptor-mediated potential, as measured both extracellularly and intracellularly. This depression, which was also induced by peroxyvanadate, required synaptic stimulation to be induced, and was tyrosine kinase-dependent. Our results suggest that tyrosine phosphorylation of as yet unidentified proteins is responsible for a novel activity-dependent depression of NMDA receptor function that inhibits synaptic plasticity.

Long-lasting increase in cellular excitability associated with the priming of LTP induction in rat hippocampus.

The mechanisms underlying the facilitation (priming) of long-term potentiation (LTP) by prior activation of metabotropic glutamate receptors (mGluRs) were investigated in area CA1 of rat hippocampal slices. In particular, we focused on whether a long-lasting increase in postsynaptic excitability could account for the facilitated LTP. Administration of the mGluR agonist 1S, 3R-aminocyclopentanedicarboxylic acid (ACPD) produced rapid decreases in the amplitude of both the slow spike afterhyperpolarization (AHP(slow)) and spike frequency adaptation recorded intracellularly from CA1 pyramidal cells. These changes persisted after drug washout, showing only a slow decay over 20 min. ACPD also caused a leftward shift of the field EPSP-population spike relation and an overall increase in population spike amplitude, but this effect was not as persistent as the intracellularly measured alterations in cell excitability. ACPD-treated cells showed increased spike discharges during LTP-inducing tetanic stimulation, and the amplitude of the AHP(slow) was negatively correlated with the degree of initial LTP induction. The beta-adrenergic agonist isoproterenol also caused excitability changes as recorded intracellularly, whereas in extracellular experiments it weakly primed the induction but not the persistence of LTP. ACPD primed both LTP measures. Isoproterenol administration during the tetanus occluded the priming effect of ACPD on initial LTP induction but not its effect on LTP persistence. We conclude that the persistent excitability changes elicited by ACPD contributes to the priming of LTP induction but that other ACPD-triggered mechanisms must account for the facilitated persistence of LTP in the priming paradigm.

A double dissociation within the hippocampus of dopamine D1/D5 receptor and beta-adrenergic receptor contributions to the persistence of long-term potentiation.

We compared the effects of the D1/D5 receptor antagonist SCH-23390 with the beta-adrenergic receptor antagonist propranolol on the persistence of long-term potentiation in the CA1 and dentate gyrus subregions of the hippocampus. In slices, SCH-23390 but not propranolol reduced the persistence of long-term potentiation in area CA1 without affecting its induction. The drugs exerted reverse effects in the dentate gyrus, although in this case the induction of long-term potentiation was also affected by propranolol. The lack of effect of SCH-23390 on the induction and maintenance of long-term potentiation in the dentate gyrus was confirmed in awake animals. The drug also had little or no effect on the expression of inducible transcription factors. In area CA1 of awake animals, SCH-23390 blocked persistence of long-term potentiation beyond 3 h, confirming the results in slices. To rule out a differential release of catecholamines induced by our stimulation protocols between brain areas, we compared the effects of the D1/D5 agonist SKF-38393 with the beta-adrenergic agonist isoproterenol on the persistence of a weakly induced, decremental long-term potentiation in CA1 slices. SKF-38393 but not isoproterenol promoted greater persistence of long-term potentiation over a 2-h period. In contrast, isoproterenol but not SKF-38392 facilitated the induction of long-term potentiation. These data demonstrate that there is a double dissociation of the catecholamine modulation of long-term potentiation between CA1 and the dentate gyrus, suggesting that long-term potentiation in these brain areas may be differentially consolidated according to the animal's behavioural state.

Effects of endothelin-1 on hippocampal synaptic plasticity.

We examined the effects of puff application of endothelin (ET)-1 on the induction of long-term potentiation (LTP) and heterosynaptic long-term depression (LTD) in hippocampal CA1 slices. ET-1 applied 2 min prior to tetanus blocked the induction of LTP, but facilitated the induction of heterosynaptic LTD. These ET-1 effects on synaptic plasticity were dose-dependent, and not due to a generalized depression of baseline responses. ET-1 did not alter NMDA receptor-mediated responses. These data provide the first evidence that endothelin modulates activity-dependent synaptic plasticity, and the potency of these effects suggests that endogenous ET-1 may play an important role in regulating memory storage processes.

Glucocorticoid receptor activation lowers the threshold for NMDA-receptor-dependent homosynaptic long-term depression in the hippocampus through activation of voltage-dependent calcium channels.

The effects of the glucocorticoid receptor agonist RU-28362 on homosynaptic long-term depression (LTD) were examined in hippocampal slices obtained from adrenal-intact adult male rats. Field excitatory postsynaptic potentials were evoked by stimulation of the Schaffer collateral/commissural pathway and recorded in stratum radiatum of area CA1. Low-frequency stimulation (LFS) was delivered at LTD threshold (2 bouts of 600 pulses, 1 Hz, at baseline stimulation intensity). LFS of the Schaffer collaterals did not produce significant homosynaptic LTD in control slices. However, identical conditioning in the presence of the glucocorticoid receptor agonist RU-28362 (10 microM) produced a robust LTD, which was blocked by the selective glucocorticoid antagonist RU-38486. The LTD induced by glucocorticoid receptor activation was dependent on N-methyl-D-aspartate (NMDA) receptor activity, because the specific NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) blocked the facilitation. However, the facilitation of LTD was not due to a potentiation of the isolated NMDA receptor potential by RU-28362. The facilitation of LTD by RU-28362 was also blocked by coincubation of the L-type voltage-dependent calcium channel (VDCC) antagonist nimodipine. Selective activation of the L-type VDCCs by the agonist Bay K 8644 also facilitated LTD induction. Both nimodipine and D-AP5 were effective in blocking the facilitation of LTD by Bay K 8644. These results indicate that L-type VDCCs can contribute to NMDA-receptor-dependent LTD induction.

Protein kinase and phosphatase activity regulate the form of synaptic plasticity expressed.

Long-term potentiation (LTP) and long-term depression (LTD) are calcium-dependent forms of synaptic plasticity observed in area CA1 of the hippocampus. Low-frequency tetani (1-5 Hz) activates protein phosphatases to induce LTD, whereas high-frequency tetani (> 25 Hz) activates protein kinases to induce LTP. A tetanus at an intermediate frequency (10 Hz), however, does not result in a change in synaptic efficacy [Dudek and Bear, (1992), Proc. Natl. Acad. Sci. USA, 89:4363-4367]. We hypothesized that the 10-Hz tetanus results in no long-term change in synaptic efficacy due to a balance of the activity of protein phosphatases and protein kinases. We manipulated protein kinase/phosphatase activity at a 10-Hz tetanus to test this hypothesis. A 10-Hz tetanus under normal conditions results in a transient depression which returns to baseline in 25 min. However, inhibiting kinase activity with the protein kinase inhibitor H-7, or decreasing extracellular calcium concentration, results in the 10-Hz tetanus, inducing LTD. Conversely, inhibiting phosphatase activity with the protein phosphatase inhibitor tautomycin, or increasing extracellular calcium concentration, results in the 10-Hz tetanus, inducing LTP. These results suggest that the relative balance of protein kinase and phosphatase activity (and/or the calcium levels activating them) determines the expression of specific forms of synaptic plasticity, and that these forms lie on a continuum.

Long-term potentiation induces synaptic plasticity at nontetanized adjacent synapses.

The two forms of long-term potentiation (LTP) and one form of long-term depression (LTD) in hippocampal area CA1 are induced by different afferent tetani: LTD is induced by a 3- to 5-Hz tetanus, whereas higher frequencies are necessary for LTP mediated by NMDA receptors (25- to 50-Hz tetanus) and LTP mediated by voltage-dependent calcium channels (200-Hz tetanus). It has been suggested that the three forms are induced by graded increases in postsynaptic calcium, with LTD being induced at the lowest calcium concentration. We hypothesized that synapses near a site of LTP induction would elicit LTD owing to diffusion of calcium or its binding proteins. This was tested using a fixed multistimulating electrode array spanning stratum radiatum in area CA1 of rat hippocampal slices. The tetanized sites all displayed LTP. Nontetanized sites displayed LTD following a 50-Hz tetanus, whereas LTD was often seen following a 200-Hz tetanus. In most instances pEPSP and population spike responses were similar; however, EPSP/spike dissociations (LTD of EPSP, LTP of spike) were seen following activation of NMDA receptors by 50-Hz and 200-Hz tetani. The results are discussed with respect to mechanisms of action and functional significance.