Interferon-α and interferon-γ production capacity of idiopathic isolated optic neuritis patients

Interferon-α and interferon-γ production by idiopathic isolated optic neuritis (ON) patients was studied. The production capacity was compared with that in two control groups: patients with iritis and healthy control subjects. A sensitive and reliable interferon bioassay was applied for interferon level measurements.Statistically significant differences were not found between patients and control groups in either interferon-α production or interferon-γ production.     

Effects of 5α-dihydrocorticosterone on evoked responses and long-term potentiation

The effect of a Ring A-reduced metabolite of corticosterone, 5 alpha-dihydrocorticosterone (DHB) on long-term potentiation (LTP) in the dentate gyrus (DG) of the rat were studied in barbiturate-anaesthetised animals. It was observed that DHB significantly impairs the development of LTP, more particularly the population spike (PS) component of the evoked potential (EP) to perforant path (PP) stimulation. Nutralipid, an inert control solvent of the steroid, did not affect LTP development. We argue that both, membrane and intracellular effects of DHB, are involved in the mechanisms responsible for DHB blocking of LTP.     

Nicotine accelerates reversal of long-term potentiation and enhances long-term depression in the rat hippocampal CA1 region

In the hippocampal CA1 region, low-frequency stimulation (LFS; 200 pulses at 1 Hz) causes reversal of long-term potentiation (depotentiation, DP) and long-term depression (LTD), both of which are thought to be the cellular substrate of learning and memory. Because nicotine enhances learning and memory, we examined if nicotine modulates DP and LTD in the hippocampal CA1 region. Bath application of nicotine during LFS accelerated DP, that is, potentiated synaptic responses in hippocampal CA1 neurons returned to pre-tetanic control levels more rapidly in the presence of nicotine. Because a similar acceleration of DP was observed using the alpha7 nicotinic acetylcholine receptor (nAChR)-selective antagonist methyllcaconitine (MLA), the nicotine effect appeared to be at least partly mediated by nicotine-induced desensitization of alpha7 nAChRs. Delivery of LFS in the presence of nicotine or MLA also depressed synaptic responses in a naive pathway and facilitated LTD, that is, the magnitude of LTD was larger when the drug was present during LFS. Thus, these results demonstrate that nicotine facilitates DP and LTD, which may represent, at least in part, the cellular mechanism underlying nicotine-induced cognitive enhancement.     

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.     

Interferon-γ enhances the expression of retinal S-antigen, a specific neuronal cel marker

Interferon-γ (IFN-γ) is a potent lymphokine which can modify a variety of cellular processes. One of the mechanisms involved in these processes is the ability of IFN-γ to alter the regulation and expression of cellular proteins. Using analytical flow cytometry, we show that recombinant human IFN-γ can enhance the expression or retinal S-antigen in retinoblastoma cells. This enhancement was selective since two other retinal cell proteins, interphotoreceptor binding protein (IRBP) and photo-6, were not affected by IFN-γ treatment. Retinal S-antigen plays an important role in vision and is one of the retinal proteins capable of inducing an inflammatory eye disease called experimental autoimmune uveitis. These studies therefore demonstrate an important role for this lymphokine, that is, the enhanced expression of a neuronal cell protein. This finding may also identify additional mechanisms by which IFN-γ may participate in immunopathologic events in nervous tissue.     

Potassium-induced long-term potentiation in rat hippocampal slices

We observed that a transient increase in extracellular potassium concentration (50 mM for 40 s) was sufficient to induce long-term potentiation (LTP) of synaptic transmission in area CA1 of the hippocampal slice. Potassium-induced potentiation of the Schaffer collateral/commissural synapses demonstrated several features characteristic of tetanus-induced LTP: (1) population excitatory post-synaptic potential (EPSP) amplitudes were enhanced to a similar magnitude (on average 70% above baseline) which (2) lasted for more than 20 min; (3) induction was blocked by bath application of the specific N-methyl-d-aspartate (NMDA) receptor antagonistd-2-amino-5-phosphonovalerate (d-APV), and (4) was attenuated by reduction of the concentration of calcium in the extracellular medium. Induction of either potassium-induced LTP or tetanus-induced LTP occluded the subsequent expression of the other. Finally, exposure to high potassium in the absence of electrical stimulation was sufficient to induce LTP. Taken together, these data indicate that brief depolarizing stimuli other than tetanus can induce LTP. Because potassium-induced LTP is not restricted to the subset of afferents examined electrophysiologically, such a method could facilitate analyses of the biochemical events underlying both the induction and expression of LTP.     

Opioid receptor-dependent long-term potentiation at the lateral perforant path-CA3 synapse in rat hippocampus

The involvement of opioid receptors in the induction of long-term potentiation (LTP) was investigated in the lateral and medial perforant path projections to area CA3 of the hippocampus in anesthetized rats. The opioid receptor antagonist naloxone (10 nmol), applied to the hippocampal CA3 region 10 min prior to tetanization, blocked the induction lateral perforant path-CA3 LTP induced by high-frequency stimulation. By contrast, LTP induction in medial perforant path-CA3 was not attenuated by a 10 nmol quantity of naloxone. (+)-Naloxone (10 nmol), the inactive stereoisomer of naloxone, was without effect on the induction of lateral perforant path-CA3 LTP. Naloxone applied l h following LTP induction did not reverse established lateral perforant path-CA3 LTP, indicating that opioid receptors are involved in the induction but not the maintenance of LTP in this pathway. LTP of medial perforant path responses developed immediately, while LTP of lateral perforant path responses was slow to develop. The latter pattern is similar to the time course of the development of LTP observed at the mossy fiber-CA3 synapse and suggests that lateral and medial perforant path synapses may use distinct mechanisms of both induction and expression of LTP. These data extend previous findings demonstrating opioid receptor-dependent mechanisms of LTP induction at both the mossy fiber-CA3 synapse and the lateral perforant path-dentate gyms synapse. We suggest that lateral perforant path and mossy fiber synapses may utilize similar, opioid receptor-dependent, mechanisms of LTP induction and expression.     

Minor role for α1-adrenoceptors in the facilitation of induction and early maintenance of long-term potentiation in the CA1 field of the hippocampus

The influences of noradrenaline on the modulation of learning and memory functions, as well as synaptic plasticity, e.g., long-term potentiation (LTP), via β-adrenoceptors are well documented, whereas the role of α₁-adrenoceptors has not been studied extensively. Therefore, the effects of α₁-agonists (ST 587 and methoxamine) on the induction of LTP were examined in the CA1 area of the hippocampus in vitro. Submaximal LTP in extracellular excitatory postsynaptic potentials (EPSP) was induced with theta burst stimulation using 4 bursts. The effects of a β-agonist, isoproterenol, on synaptic potentiation were studied as a comparison in this preparation. At a concentration of 1 μM, ST 587 slightly increased the magnitude of potentiation in EPSPs (measured 30 min after stimulation) compared to a control pathway potentiated 30 min before drug infusion, whereas a lower concentration (0.3 μM) was not effective. Methoxamine did not induce any increase in the amount of submaximal LTP at concentrations of 0.3, 1.0, or 3.0 μM. Isoproterenol (1.5 μM) increased the amount of LTP when measured 30 min after stimulation, and also transiently increased synaptic transmission, measured both in the slope and amplitude of the field EPSP in the prepotentiated control pathway. Thus, the present results indicate that (1) α₁-adrenoceptors have only a minor role in hippocampal synaptic plasticity in the CA1 area, but (2) the synaptic plasticity in the CA1 area of the hippocampus assessed by induction and early maintenance of LTP in vitro can be modulated through β-adrenoceptors. J. Neurosci. Res. 51:309–315, 1998. © 1998 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.     

Interferon-γ secretion by in vivo activated cytotoxic T lymphocytes from the blood and cerebrospinal fluid during mumps meningitis

Functional studies of cerebrospinal fluid T lymphocytes during acute viral infections of the nervous system are rare. Recently, we had the opportunity to investigate the requirments for interferon-γ (IFN-γ) production of human in vivo activated (primary) cytotoxic T lymphocytes (CTL) generated during acute viral meningitis. Two HLA-B7-restricted, CD4⁻, CD8⁺ CTL clones from cerebrospinal fluid of one patient with mumps meningitis were studied. Although lytic activity was restricted by HLA-B7, the clones produced similar amounts of IFN-γ when stimulated with HLA-matched and mismatched mumps virus-infected target cells. In addition, peripheral blood mononuclear cells of infected patients secreted significant amounts of IFN-γ when incubated with autologous or allogeneic (HLA-A/B-mismatched) mumps virus-infected target cells. T cells capable of lytic activity and IFN-γ secretion could only be isolated from venous blood during the initial phase of the infection. We suggest that the ability of human in vivo activated CTL to secrete INF-γ early during the course of inflammation and in a HLA-unrestricted fashion is important for the elimination of viruses invading the central nervous system.     

PB-2, a polysaccharide fraction from lichen Flavoparmelia baltimorensis,peripherally promotes the induction of long-term potentiation in the rat dentate gyrus in vivo

We have previously found that oral or intravenous administration of PC-2, a polysaccharide fraction purified from extracts of lichen Flavoparmelia caperata, facilitates the induction of long-term potentiation (LTP) in the dentate gyrus of anesthetized rats. PC-2 could be useful in the development of therapeutic drugs for senile dementia. However, it has been very difficult to obtain the material Flavoparmelia caperata because of its scarcity. In the present study, we therefore investigated whether PB-2, a polysaccharide fraction from another lichen Flavoparmelia baltimorensis, has similar biological effects. Oral administration of PB-2 (100-200 mg/kg) did not affect basal evoked potentials, but significantly promoted the induction of LTP following tetanic stimulation (30 pulses at 60 Hz) in the dentate gyrus of anesthetized rats. Intravenous injection of PB-2 (1-5 mg/kg) was also effective in promoting the induction of LTP, but intracerebroventricular injection of PB-2 (1-2 mg/brain) was ineffective. PB-2, as well as PC-2, should be valuable in identifying factors that promote synaptic plasticity in the hippocampus.     

Inositol 1-phosphate formation in long-term potentiation and kindling

Long-term potentiation (LTP) in the CA3 hippocampal subfield, elicited in vivo, produced significant increases in basal and in carbachol- and noradrenaline-induced hydrolysis of phosphatidylinositol-4,5-biphosphate (PtdIns(4,5)P2) as measured by the accumulation of InsP1 in hippocampal slices in vitro. Kindling, however, resulted in significant decreases in basal and in carbachol- and noradrenaline-induced accumulation of InsP1 in hippocampal slices. N-Methyl-D-aspartate (NMDA) receptors do not directly alter the hydrolysis of PtdIns(4,5)P2 in either LTP or kindling. These results demonstrate that LTP and kindling are associated with opposite alterations in efficacy of the main receptors mediating the hydrolysis of PtdIns(4,5)P2.     

Developmental changes in long-term potentiation in CA1 of rat hippocampal slices

Long-term potentiation (LTP) was examined in the CA1 region of rat hippocampal slices at postnatal day 9 (P9), P15, P30, P60, P90, P120, and P300. A single 100 Hz × 1 sec tetanus failed to induce LTP in P9 slices, while similar degrees of LTP were observed at P15, P30, and P60. At P30, changes in population spike (PS) amplitudes were accurately predicted by changes in dendritic excitatory postsynaptic potentials (EPSPs). However, at P15, the predicted increase in PS calculated from corresponding changes in dendritic EPSPs was significantly less than the observed increase, suggesting that EPSP-PS dissociation (ES-dissociation) plays a substantial role in LTP at P15. Additionally, the corresponding changes in somatic EPSP height measured in the CA1 cell layer did not predict the E-S dissociation at P15, suggesting that the E-S dissociation arises largely from changes in the excitability of the soma. Using a single 100 Hz × 1 sec tetanus, LTP proved difficult to induce in slices from rats ≥ P90, with slices showing initial enhancement that faded over 60 min of monitoring. © 1995 Wiley-Liss, Inc.     

Dopaminergic DA1 signaling couples growth-associated protein-43 and long-term potentiation in guinea pig hippocampus

The basic goal of the project was to determine whether dopaminergic DA1 receptor (DA1R) signaling couples growth-associated protein 43 (GAP-43; a putative "plasticity" protein) and long-term potentiation (LTP; an enduring form of synaptic plasticity). Thus, guinea pigs were prepped to stimulate the CA3 and evoke population spikes in the CA1 neurons in the hippocampus in vivo. Animals were injected with either saline or SCH23390 (a selective DA1R antagonist), 1-2 h prior to recordings. It was found that tetanic stimulation (100 Hz, 1 s, three trains at 15 s intervals) readily produced early-LTP and late-LTP in the saline group. In contrast, none of the guinea pigs pre-treated with SCH23390 developed late-LTP, though early-LTP had been present. Furthermore, both GAP-43 mRNA and protein were up-regulated after LTP induction in the saline group. However, GAP-43 protein up-regulation was blocked in animals treated with SCH23390. Anti-GAP-43 immunoreactivity was intense in CA3/CA1 synaptic regions, whereas GAP-43 mRNA hybridization was localized to somatic layers in the hippocampus. Altogether, our results suggest that dopaminergic DA1 signaling partly couples GAP-43 and LTP.     

The effects of anticonvulsant drugs on long-term potentiation (LTP) in the rat hippocampus

In hippocampal CA1 area, there are at least two forms of long-term potentiation (LTP): one is N-methyl-D-aspartate (NMDA) receptor-dependent LTP (NMDA LTP), which is induced with a 25 Hz tetanus and blocked by 50 μM 2-amino-5-phosphonovaleric acid (APV); the other is NMDA receptor-independent LTP (VDCC LTP), which is induced by 200 Hz tetanus stimulation in the presence of APV and blocked by nifedipine, a voltage-dependent Ca⁺⁺ channel (VDCC) blocker, or by the intracellular injection of 1,2-bis(2-Aminophenoxoy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA). The effects of anticonvulsant drugs phenobarbital, phenytoin, and valproic acid on both NMDA LTP and VDCC LTP were investigated in rat hippocampal slices. The results showed that 0.1 mg/ml valproic acid significantly altered baseline population spike amplitude by 34.6%, but the other drugs had no significant effect on the baseline population spike amplitude. Phenobarbital (0.025 mg/ml) potently blocked NMDA LTP and inhibited VDCC LTP. Phenytoin (0.02 mg/ml) had no effect on NMDA LTP but reduced VDCC LTP. Valproic acid did not inhibit VDCC LTP, but it abolished the expression of NMDA LTP in a similar manner as H-7, a nonspecific protein kinase C inhibitor. These data suggest that the anticonvulsant effects of these three drugs may be via different cellular mechanisms.     

NCAM-antibodies modulate induction of long-term potentiation in rat hippocampal CA1

The neural cell adhesion molecule (NCAM) probably plays a role in neural plasticity in the adult vertebrate brain. We here present evidence that NCAM may be involved in long-term potentiation (LTP) in the CA1-region of rat hippocampal slices. It is shown that local application of antibodies against NCAM inhibits subsequent LTP-induction. Thus NCAM may be directly involved in the initial phase of LTP-induction. These results have important implications for the possible involvement of NCAM in learning and memory.     

Heterosynaptic long-term depression is facilitated by blockade of inhibition in area CA1 of the hippocampus

Non-associative long-term depression (LTD) of the stratum radiatum input to area CA1 was studied in rat hippocampal slices. Tetanization of either the alveus or stratum oriens produced > 30min depression of the radiatum field EPSP and population spike, but generally only in the presence of picrotoxin. The spike depression was accounted for by the EPSP depression, and could be blocked by prior administration of anN-methyl-d-aspartate receptor antagonist. These data suggest that the induction of non-associative LTD is depolarization-dependent and involves theN-methyl-d-aspartate receptor/channel complex.     

Only ‘de novo’ long-term depression (LTD) in the rat hippocampus in vitro is blocked by the same low concentration of FK506 that blocks LTD in the visual cortex

It has been proposed that the long-term depression (LTD) seen following low frequency stimulation (LFS) in the rat hippocampus involves calcineurin. We have tested this by examining the effect of FK506, a macrolide which blocks calcineurin at nanomolar concentrations, on synaptic transmission in the rat hippocampal slice at a concentration of 1 μM which has been shown to block LTD in the visual cortex. The effect of FK506 on long-term potentiation (LTP) and spontaneous transmitter release was also studied. The magnitude of LTD induced by LFS was 16.7 ± 2.4% in control which was not significantly different from the 22.3 ± 3.0% seen in the same preparations after exposure to FK506 for 25–30 min. In contrast the magnitude of LTD induced ‘de novo’ in preparations exposed to FK506 was significantly reduced. FK506 had no significant effect on LTP, miniature EPSP frequency, miniature EPSP amplitude, resting membrane potential or input resistance. These results, therefore, support the hypothesis that calcineurin is involved in ‘de novo’ LTD but it appears that an event is triggered by LFS whereby FK506-insensitive LTD can subsequently be activated by a second episode of LFS.     

The non-steroidal anti-inflammatory drug diclofenac sodium attenuates IFN-α induced alterations to monoamine turnover in prefrontal cortex and hippocampus

Interferon-α (IFN-α) administration induces major depression in a significant number of patients undergoing treatment for viral illnesses and other chronic diseases. Non-steroidal anti-inflammatory drugs (NSAIDs) are known to counteract a number of IFN-α-induced side effects, including pro-inflammatory cytokine activation and stress hormone release. To investigate this possibility further, we sought to determine the effect of the NSAID diclofenac sodium on monoamine turnover in brain induced by acute IFN-α exposure. Eleven male, Wistar rats (8 weeks old) were pretreated with diclofenac (20 mg/kg, s.c.) or saline, followed by intracerebroventricular (i.c.v.) infusion of IFN-α (1000 IU in 5 μl) or vehicle. The prefrontal cortex, striatum, and hippocampus were isolated and samples were assayed for monoamines and major metabolites by high-pressure liquid chromatography with electrochemical detection. The data show that acute IFN-α increased serotonin turnover in prefrontal cortex and increased dopamine turnover in hippocampus, while pre-treatment with diclofenac completely prevented these neurochemical responses. Importantly, these changes were recorded in two brain areas known to be important in depression and antidepressant action. These data offer support for a novel role of NSAIDs in modulating IFN-α-induced neurochemical alterations, and raise the possibility of the use of NSAIDs for the prevention of IFN-α-induced depression.