Small-molecule conversion of toxic oligomers to nontoxic ß-sheet-rich amyloid fibrils.

Several lines of evidence indicate that prefibrillar assemblies of amyloid-ß (Aß) polypeptides, such as soluble oligomers or protofibrils, rather than mature, end-stage amyloid fibrils cause neuronal dysfunction and memory impairment in Alzheimer's disease. These findings suggest that reducing the prevalence of transient intermediates by small molecule-mediated stimulation of amyloid polymerization might decrease toxicity. Here we demonstrate the acceleration of Aß fibrillogenesis through the action of the orcein-related small molecule O4, which directly binds to hydrophobic amino acid residues in Aß peptides and stabilizes the self-assembly of seeding-competent, ß-sheet-rich protofibrils and fibrils. Notably, the O4-mediated acceleration of amyloid fibril formation efficiently decreases the concentration of small, toxic Aß oligomers in complex, heterogeneous aggregation reactions. In addition, O4 treatment suppresses inhibition of long-term potentiation by Aß oligomers in hippocampal brain slices. These results support the hypothesis that small, diffusible prefibrillar amyloid species rather than mature fibrillar aggregates are toxic for mammalian cells.

Plasticity of NMDA receptor-mediated excitatory postsynaptic currents at perforant path inputs to dendrite-targeting interneurons.

Synaptic plasticity of NMDA receptors (NMDARs) has been recently described in a number of brain regions and we have previously characterised LTP and LTD of glutamatergic NMDA receptor-mediated EPSCs (NMDAR-EPSCs) in granule cells of dentate gyrus. The functional significance of NMDAR plasticity at perforant path synapses on hippocampal network activity depends on whether this is a common feature of perforant path synapses on all postsynaptic target cells or if this plasticity occurs only at synapses on principal cells. We recorded NMDAR-EPSCs at medial perforant path synapses on interneurons in dentate gyrus which had significantly slower decay kinetics compared to those recorded in granule cells. NMDAR pharmacology in interneurons was consistent with expression of both GluN2B- and GluN2D-containing receptors. In contrast to previously described high frequency stimulation-induced bidirectional plasticity of NMDAR-EPSCs in granule cells, only LTD of NMDAR-EPSCs was induced in interneurons in our standard experimental conditions. In interneurons, LTD of NMDAR-EPSCs was associated with a loss of sensitivity to a GluN2D-selective antagonist and was inhibited by the actin stabilising agent, jasplakinolide. While LTP of NMDAR-EPSCs can be readily induced in granule cells, this form of plasticity was only observed in interneurons when extracellular calcium was increased above physiological concentrations during HFS or when PKC was directly activated by phorbol ester, suggesting that opposing forms of plasticity at inputs to interneurons and principal cells may act to regulate granule cell dendritic integration and processing.

Inhibition of the slow afterhyperpolarization restores the classical spike timing-dependent plasticity rule obeyed in layer 2/3 pyramidal cells of the prefrontal cortex.

The induction of long-term potentiation (LTP) and long-term depression (LTD) of excitatory postsynaptic currents was investigated in proximal synapses of layer 2/3 pyramidal cells of the rat medial prefrontal cortex. The spike timing-dependent plasticity (STDP) induction protocol of negative timing, with postsynaptic leading presynaptic stimulation of action potentials (APs), induced LTD as expected from the classical STDP rule. However, the positive STDP protocol of presynaptic leading postsynaptic stimulation of APs predominantly induced a presynaptically expressed LTD rather than the expected postsynaptically expressed LTP. Thus the induction of plasticity in layer 2/3 pyramidal cells does not obey the classical STDP rule for positive timing. This unusual STDP switched to a classical timing rule if the slow Ca(2+)-dependent, K(+)-mediated afterhyperpolarization (sAHP) was inhibited by the selective blocker N-trityl-3-pyridinemethanamine (UCL2077), by the ß-adrenergic receptor agonist isoproterenol, or by the cholinergic agonist carbachol. Thus we demonstrate that neuromodulators can affect synaptic plasticity by inhibition of the sAHP. These findings shed light on a fundamental question in the field of memory research regarding how environmental and behavioral stimuli influence LTP, thereby contributing to the modulation of memory.

Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo.

One of the most clinically advanced forms of experimental disease-modifying treatment for Alzheimer disease is immunization against the amyloid beta protein (Abeta), but how this may prevent cognitive impairment is unclear. We hypothesized that antibodies to Abeta could exert a beneficial action by directly neutralizing potentially synaptotoxic soluble Abeta species in the brain. Intracerebroventricular injection of naturally secreted human Abeta inhibited long-term potentiation (LTP), a correlate of learning and memory, in rat hippocampus in vivo but a monoclonal antibody to Abeta completely prevented the inhibition of LTP when injected after Abeta. Size fractionation showed that Abeta oligomers, not monomers or fibrils, were responsible for inhibiting LTP, and an Abeta antibody again prevented such inhibition. Active immunization against Abeta was partially effective, and the effects correlated positively with levels of antibodies to Abeta oligomers. The ability of exogenous and endogenous antibodies to rapidly neutralize soluble Abeta oligomers that disrupt synaptic plasticity in vivo suggests that treatment with such antibodies might show reversible cognitive deficits in early Alzheimer disease.

GluN2B subunit-containing NMDA receptor antagonists prevent Abeta-mediated synaptic plasticity disruption in vivo.

Currently, treatment with the relatively low-affinity NMDA receptor antagonist memantine provides limited benefit in Alzheimer's disease (AD). One probable dose-limiting factor in the use of memantine is the inhibition of NMDA receptor-dependent synaptic plasticity mechanisms believed to underlie certain forms of memory. Moreover, amyloid-beta protein (Abeta) oligomers that are implicated in causing the cognitive deficits of AD potently inhibit this form of plasticity. Here we examined if subtype-preferring NMDA receptor antagonists could preferentially protect against the inhibition of NMDA receptor-dependent plasticity of excitatory synaptic transmission by Abeta in the hippocampus in vivo. Using doses that did not affect control plasticity, antagonists selective for NMDA receptors containing GluN2B but not other GluN2 subunits prevented Abeta(1-42) -mediated inhibition of plasticity. Evidence that the proinflammatory cytokine TNFalpha mediates this deleterious action of Ass was provided by the ability of TNFalpha antagonists to prevent Abeta(1-42) inhibition of plasticity and the abrogation of a similar disruptive effect of TNFalpha using a GluN2B-selective antagonist. Moreover, at nearby synapses that were resistant to the inhibitory effect of TNFalpha, Abeta(1-42) did not significantly affect plasticity. These findings suggest that preferentially targeting GluN2B subunit-containing NMDARs may provide an effective means of preventing cognitive deficits in early Alzheimer's disease.

Extrasynaptic NR2D-containing NMDARs are recruited to the synapse during LTP of NMDAR-EPSCs.

Long-term potentiation of NMDA-receptor-mediated synaptic transmission (NMDAR-LTP) is a little-understood form of plasticity. In the present study, we investigated whether NMDAR-LTP in the dentate gyrus involves recruitment of extrasynaptic NMDARs, because NMDARs are expressed both synaptically and extrasynaptically with evidence for subtype differences at different locations. We show that before induction of NMDAR-LTP, pharmacological inhibition of glutamate transporters resulted in glutamate spillover from the synapse and activation of extrasynaptic NMDARs. After the induction of NMDAR-LTP, such activation of extrasynaptic NMDARs was absent. Activation of extrasynaptic NMDARs after glutamate uptake inhibition also occurred when synaptic NMDARs were inhibited with MK801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate], and this extrasynaptically mediated NMDAR-EPSC was strongly reduced by prior induction of NMDAR-LTP. The extrasynaptic NMDARs were shown to be NR2D-containing, because the activation of extrasynaptic NMDARs by glutamate spillover was prevented by the NR2D-selective antagonists PPDA [(2R*,3S*)-1-(phenanthrenyl-2-carbonyl)piperazine-2,3-dicarboxylic acid] and UBP141. Further studies using selective antagonists for NR2A- and NR2B-containing NMDARs demonstrated that synaptic NMDARs are predominantly NR2A-containing and NR2B-containing receptors, whereas the extrasynaptic NMDARs are complex multimeric receptors with NR2A, NR2B, or NR2D subunits. Our results show that LTP of NMDAR-EPSCs involves movement of NMDARs from an extrasynaptic to a synaptic location and suggest a novel physiological role for extrasynaptic NMDARs.

Amyloid beta protein dimer-containing human CSF disrupts synaptic plasticity: prevention by systemic passive immunization.

The current development of immunotherapy for Alzheimer's disease is based on the assumption that human-derived amyloid beta protein (Abeta) can be targeted in a similar manner to animal cell-derived or synthetic Abeta. Because the structure of Abeta depends on its source and the presence of cofactors, it is of great interest to determine whether human-derived oligomeric Abeta species impair brain function and, if so, whether or not their disruptive effects can be prevented using antibodies. We report that untreated ex vivo human CSF that contains Abeta dimers rapidly inhibits hippocampal long-term potentiation in vivo and that acute systemic infusion of an anti-Abeta monoclonal antibody can prevent this disruption of synaptic plasticity. Abeta monomer isolated from human CSF did not affect long-term potentiation. These results strongly support a strategy of passive immunization against soluble Abeta oligomers in early Alzheimer's disease.

Intracellular mechanisms underlying the nicotinic enhancement of LTP in the rat dentate gyrus.

We have previously shown that activation of nicotinic acetylcholine receptors (nAChRs) enhanced long-term potentiation (LTP) in the rat dentate gyrus in vitro via activation of alpha7 nAChR. In the present studies, mechanisms underlying the acute and chronic nicotinic enhancement of LTP were examined. In particular, the involvement of activation of intracellular kinases was examined using selective kinase antagonists, and the effects of enhancing cholinergic function with positive allosteric modulators of the alpha7 nAChR and with acetylcholinesterase (AChE) inhibitors were also investigated. Activation of extracellular signal-regulated kinase (ERK) and cAMP-dependent protein kinase (PKA) was found to be involved in the induction of the acute nicotinic enhancement of LTP, although not control LTP. In contrast, activation of the tyrosine kinase Src, Ca(2+)-calmodulin-dependent protein kinase II, Janus kinase 2 and p38 mitogen-activated protein kinase was not involved in the acute nicotinic enhancement of LTP, although Src activation was necessary for control LTP. Moreover, activation of phosphoinositide 3-kinase was involved in the acute nicotinic enhancement of LTP to a much lesser extent than in control LTP. Chronic nicotine enhancement of LTP was found to be dependent on PKA, ERK and Src kinases. Acute nicotinic enhancement of LTP was occluded by chronic nicotine treatment. The positive allosteric modulator PNU-120596 was found to strongly reduce the threshold for nicotinic enhancement of LTP, an affect mediated via the alpha7 nAChR as it was blocked by the selective antagonist methyllycaconitine. The AChE inhibitors tacrine and physostigmine enhanced control LTP.

Remodelling by early-life stress of NMDA receptor-dependent synaptic plasticity in a gene-environment rat model of depression.

An animal model of depression combining genetic vulnerability and early-life stress (ELS) was prepared by submitting the Flinders Sensitive Line (FSL) rats to a standard paradigm of maternal separation. We analysed hippocampal synaptic transmission and plasticity in vivo and ionotropic receptors for glutamate in FSL rats, in their controls Flinders Resistant Line (FRL) rats, and in both lines subjected to ELS. A strong inhibition of long-term potentiation (LTP) and lower synaptic expression of NR1 subunit of the NMDA receptor were found in FSL rats. Remarkably, ELS induced a remodelling of synaptic plasticity only in FSL rats, reducing inhibition of LTP; this was accompanied by marked increase of synaptic NR1 subunit and GluR2/3 subunits of AMPA receptors. Chronic treatment with escitalopram inhibited LTP in FRL rats, but this effect was attenuated by prior ELS. The present results suggest that early gene-environment interactions cause lifelong synaptic changes affecting functional and molecular aspects of plasticity, partly reversed by antidepressant treatments.

Cyclooxygenase-2 inhibition improves amyloid-beta-mediated suppression of memory and synaptic plasticity.

Non-steroidal anti-inflammatory agents (NSAIDs) are associated with a marked reduction in the risk of developing Alzheimer's disease, a form of dementia characterized by the accumulation of amyloid plaques containing the amyloid-beta protein (Abeta). Studies of the effects of NSAIDs upon the inflammatory response surrounding amyloid plaques and upon the generation of Abeta from the amyloid precursor protein (APP) have led to two proposed mechanisms by which NSAIDs may protect against Alzheimer's disease: one, the selective lowering of Abeta42 by a subset of NSAIDs; and two, the reduction of inflammation. Although Alzheimer's disease is a disorder of brain and synaptic function, the effects of NSAIDs on Abeta-mediated suppression of synaptic plasticity and memory function have never been reported. We therefore investigated how three different NSAIDs, chosen for their distinct effects on Abeta42 production and the inhibition of the cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, affect memory function and synaptic plasticity. By focusing upon brain and synapse function, we made novel observations about the effects of NSAIDs on Abeta-mediated neural processes. Here we report that the selective inhibition of COX-2, but not COX-1, acutely prevented the suppression of hippocampal long-term plasticity (LTP) by Abeta. The non-selective NSAIDs, ibuprofen and naproxen, and a selective COX-2 inhibitor, MF-tricyclic, each restored memory function in Tg2576 mice over-expressing APP, and also blocked Abeta-mediated inhibition of LTP. There was no advantage of ibuprofen, a selective Abeta42-lowering agent (SALA), over the non-SALAs, naproxen and MF-tricyclic. The beneficial effects on memory did not depend upon lowered levels of Abeta42 or the inflammatory cytokines, tumour necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta). Intriguingly, improved memory function was inversely related to prostaglandin E2 (PGE2) levels. Conversely, exogenous PGE2 prevented the restorative effects of COX-2 inhibitors on LTP. The data indicate that the inhibition of COX-2 blocks Abeta-mediated suppression of LTP and memory function, and that this block occurs independently of reductions in Abeta42 or decreases in inflammation. The results lead us to propose a third possible mechanism by which NSAIDs may protect against Alzheimer's disease, involving the blockade of a COX-2-mediated PGE2 response at synapses.

5-HT2 receptor-mediated reversal of the inhibition of hippocampal long-term potentiation by acute inescapable stress.

The serotonergic system is known to modulate and mediate many of the central nervous system effects of stress. Here we investigated the ability of serotonergic agents to reverse the inhibition of the induction of hippocampal long-term potentiation (LTP) caused by prior exposure to inescapable stress. Elevated platform stress prevented the induction of LTP in the CA1 area of anaesthetized rats. An agent that increases extracellular 5-HT concentration, fenfluramine (5 mg/kg, i.p.) enabled the induction of LTP in previously stressed animals. Consistent with a role for enhanced activation of 5-HT(2) receptors, the facilitatory effect of fenfluramine was prevented by the 5-HT(2) receptor antagonist cinanserin (30 mg/kg). Agents that directly activate 5-HT(2) receptors, including the 5-HT(2B) receptor agonist BW 723C86 (30 mg/kg) and the 5-HT(2C) receptor agonist MK-212 (3 mg/kg), mimicked the restorative effect of fenfluramine. Fenfluramine also opposed inhibition of LTP caused by the NMDA-receptor antagonist D-AP5 (100 nmol, i.c.v.) which suggests that the facilitatory action of serotonergic agents is not restricted to stress-mediated inhibition of LTP. These findings support an important role for activation of 5-HT(2) receptors by systemically applied agents to enable recovery from the inhibition of LTP by stress.

Involvement of group I mGluRs in LTP induced by strong high frequency stimulation in the dentate gyrus in vitro.

The involvement of group I metabotropic glutamate receptors (mGluRs) and ryanodine receptors was investigated in the induction of LTP induced either by application of one standard high frequency stimulation (HFS) or by strong multiple HFS in the medial perforant path to granule cell synapse of the rat dentate gyrus. Whilst a standard brief HFS induced LTP close to 50%, strong stimulation consisting of multiple HFS induced a much larger LTP. mGluR5 was found to be partially involved in the induction of the enhanced LTP induced by the strong HFS but not in the standard LTP induced by the brief HFS. Thus the mGluR5 antagonists LY341495 and MPEP partially inhibited the induction of LTP induced by strong HFS but did not inhibit LTP induced by a standard HFS. Ryanodine was found to partially inhibit LTP induced by the strong HFS but not to inhibit the standard LTP induced by the brief HFS, demonstrating the involvement of Ca-induced Ca release from ryanodine-sensitive Ca stores in the former. These studies demonstrate that the large amplitude LTP induced by strong stimulation involves additional mechanisms to the LTP induced by brief HFS, in particular involving activation of mGluR5 and RyR-sensitive Ca stores.

Induction and expression mechanisms of postsynaptic NMDA receptor-independent homosynaptic long-term depression.

The induction of long-term depression (LTD) can be divided into two main forms, one dependent upon activation of postsynaptic NMDAR, and another independent of postsynaptic NMDAR. Non-postsynaptic NMDAR-LTD (non-NMDAR-LTD) occurs in many regions of the brain, and encompasses a wide variety of induction and expression mechanisms. In this article, the induction and expression mechanisms of such LTD in over 10 brain regions are described, with a number of common mechanisms compared across a large range of types of LTD. The article describes the involvement of different presynaptic or postsynaptic receptors in the induction of non-NMDAR-LTD, especially metabotropic glutamate receptors, cannabinoid receptors and dopamine receptors. An increase in presynaptic or postsynaptic intracellular Ca concentration is a key event in induction, commonly followed by activation of certain kinases, especially PKC, p38 MAPK and ERK. Expression mechanisms are either presynaptic via a reduction in release probability, or postsynaptic involving a decrease in AMPAR via phosphorylation of a glutamate receptor subunit, especially GluR2, followed by clathrin-mediated endocytosis. Retrograde signalling from postsynaptic to presynaptic occurs when induction is postsynaptic and expression is presynaptic.

Dopamine-dependent facilitation of LTP induction in hippocampal CA1 by exposure to spatial novelty.

In addition to its role in memory formation, the hippocampus may act as a novelty detector. Here we investigated whether attention to novel events can promote the associative synaptic plasticity mechanisms believed to be necessary for storing those events in memory. We therefore examined whether exposure to a novel spatial environment promoted the induction of activity-dependent persistent increases in glutamatergic transmission (long-term potentiation, LTP) at CA1 synapses in the rat hippocampus. We found that brief exposure to a novel environment lowered the threshold for the induction of LTP. This facilitatory effect was present for a short period following novelty exposure but was absent in animals that explored a familiar environment. Furthermore, the facilitation was dependent on activation of D1/D5 receptors. These findings support an important role for dopamine-regulated synaptic plasticity in the storage of unpredicted information in the CA1 area.

Long-term depression of NMDA receptor-mediated synaptic transmission is dependent on activation of metabotropic glutamate receptors and is altered to long-term potentiation by low intracellular calcium buffering.

Synaptic plasticity of NMDA receptor (NMDAR)-mediated transmission was investigated in the rat dentate gyrus in vitro. Isolated NMDAR EPSCs were recorded from granule cells of the dentate gyrus in response to stimulation of the medial perforant path. Long-term potentiation (LTP) or long-term depression (LTD) of NMDAR EPSCs was observed in response to brief high-frequency stimulation (HFS), with the direction and extent of plasticity dependent on the concentration and type (EGTA vs BAPTA) of the intracellular Ca2+ buffer. LTD was induced in higher concentrations of EGTA and BAPTA than LTP, and BAPTA was approximately 100-fold more potent than EGTA. Although LTD was induced in a high concentration of EGTA (10 mM), a high concentration of BAPTA (10 mM) blocked both LTP and LTD. LTP of AMPA receptor (AMPAR)-EPSCs exhibited a lower dependency on Ca2+ buffering than LTP of NMDAR EPSCs, because LTP of AMPAR EPSCs was induced by HFS in high EGTA (10 mM). We also identified a role for metabotropic glutamate receptor 5 (mGluR5) in NMDAR plasticity. HFS LTD was blocked by the group I/II mGluR antagonist LY341495 ((2S)-2-amino-2-[(1S, 2S)-2-carboxycycloprop-1-yl]-3(xanth-9-yl)propanoic acid) and by the mGluR5-selective antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP). Similarly, low-frequency stimulation-induced LTD of NMDAR EPSCs was also blocked by MPEP. These findings suggest that the direction of plasticity of NMDARs is determined by the intracellular free Ca2+ concentration and is dependent on activation of mGluR5.

Beta-amyloid blocks high frequency stimulation induced LTP but not nicotine enhanced LTP.

Nicotine has been postulated to be a possible neuroprotective agent in Alzheimer's Disease (AD). In the present studies, the effect of beta-amyloid (Abeta) was investigated on the nicotine enhancement of high-frequency-induced LTP. Perfusion of nicotine substantially enhanced HFS-induced LTP in both rat and mouse dentate gyrus. The enhancing action of nicotine was mediated via alpha7 nAChRs as it was absent in mice null for alpha7 nAChR. Abeta strongly inhibited the induction of LTP in control animals, with LTP being completely inhibited at 1h post-HFS. Although Abeta also inhibited LTP in the presence of nicotine, the extent of the inhibition of LTP in nicotine perfused slices was similar to that in control, resulting in substantial LTP remaining in the presence of Abeta in the nicotine perfused slices. The nicotine enhanced LTP and the LTP remaining in the presence of Abeta and nicotine, although not the control LTP was dependent on activation of PKA. Chronic nicotine treatment also enhanced HFS-LTP recorded in acute slices taken from the nicotine-treated animals, and such LTP was only partially inhibited by Abeta. We postulate that nicotine-enhanced LTP has certain different mechanisms to that of control LTP which results in a resistance to inhibition by Abeta.

Performance- and task-dependent effects of the dopamine D1/D5 receptor agonist SKF 38393 on learning and memory in the rat.

Dopamine D(1)/D(5) receptor agonists may enhance cognition by mimicking dopamine's neurophysiological actions on the processes underlying learning and memory. The present study examined the task- and performance- dependence of the cognitive effects of a partial agonist at dopamine D(1)/D(5) receptors, SKF 38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide], in rats. Spatial working memory was assessed in a T-maze, spatial reference memory in a water maze and habituation learning in a novel environment, a hole board. The muscarinic acetylcholine receptor antagonist scopolamine (1.5 mg/kg, i.p.) was used to cause an impairment of performance of these learning tasks. Administration of SKF 38393 (6 mg/kg, i.p.) alone had no significant effect on spontaneous alternation in the T-maze, latency to escape to a hidden platform in the water maze or the habituation of spontaneous behaviour in the hole board. In contrast, in scopolamine-treated rats, whereas SKF 38393 prevented the scopolamine-induced deficit in the T-maze, it exacerbated the impairment in the water maze and did not significantly alter the disruption of habituation. These results suggest that dopamine D(1)/D(5) receptor activation has performance- and task-dependent effects on cognitive function.

Overcoming the effects of stress on synaptic plasticity in the intact hippocampus: rapid actions of serotonergic and antidepressant agents.

Acute inescapable stress dramatically affects the inducibility of plasticity at glutamatergic synapses in the intact hippocampus. The present study examined the involvement of serotonergic mechanisms in mediating and modulating the block of long-term potentiation (LTP) in the CA1 area of anesthetized rats after exposure to an elevated platform stress. Fluoxetine and fenfluramine, agents that raise hippocampal extracellular 5-HT concentration, blocked the induction of LTP in nonstressed animals, thus mimicking the effect of stress. In contrast, (+/-)-tianeptine, a drug that decreases 5-HT levels, had no effect on LTP induction in nonstressed animals. Remarkably, (+/-) administration of tianeptine after the stress rapidly overcame the block of LTP induction without affecting baseline excitatory transmission. Consistent with a reduction of 5-HT levels being responsible for this effect of tianeptine, the (-) enantiomer, which is associated with the 5-HT uptake enhancing action of (+/-)-tianeptine, also caused a recovery of the induction of LTP in previously stressed animals, whereas the relatively inactive (+) enantiomer had no effect. Furthermore, fluoxetine prevented the effect of tianeptine in stressed animals. These findings show that antidepressants have rapid and powerful interactions with the mechanisms controlling the persistence of the block of LTP by inescapable stress.

Beta-amyloid-mediated inhibition of NMDA receptor-dependent long-term potentiation induction involves activation of microglia and stimulation of inducible nitric oxide synthase and superoxide.

The mechanisms underlying the inhibition of long-term potentiation (LTP) induction by amyloidbeta-peptide (Abeta) were investigated in the medial perforant path of the rat and mouse dentate gyrus in vitro. Evidence is presented in this study that the Abeta-mediated inhibition of LTP induction involves activation of microglia and production of reactive oxygen and nitrogen species. In control slices, Abeta strongly inhibited induction of NMDA receptor-dependent (NMDAR-dependent) LTP, although not induction of NMDAR-independent LTP or long-term depression (LTD). The inhibition of NMDAR-dependent LTP was prevented by minocycline, an agent that prevents activation of microglia. The involvement of inducible nitric oxide synthase (iNOS) was shown by the inability of Abeta to inhibit LTP induction in iNOS knock-out mice and also by the ability of two iNOS inhibitors, aminoguanidine and 1400W, to prevent the Abeta-mediated inhibition of LTP induction. The Abeta-mediated inhibition of LTP induction also was prevented by the superoxide scavenger superoxide dismutase applied together with catalase. Evidence for involvement of superoxide in the action of Abeta on LTP induction was shown by the ability of an inhibitor of NADPH oxidase to prevent the Abeta-mediated inhibition of LTP induction. The study thus provides evidence that the Abeta-mediated inhibition of LTP induction involves an inflammatory-type reaction in which activation of microglia results in the production of nitric oxide and superoxide and thence possibly peroxynitrite, a highly reactive oxidant.

Group I metabotropic glutamate receptor (mGluR)-dependent long-term depression mediated via p38 mitogen-activated protein kinase is inhibited by previous high-frequency stimulation and activation of mGluRs and protein kinase C in the rat dentate gyrus in vitro.

The induction of synaptic plasticity is known to be influenced by the previous history of the synapse, a process termed metaplasticity. Here we demonstrate a novel metaplasticity in which group I metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) of synaptic transmission is regulated by previous mGluR activation. In these studies, the group I mGluR-dependent LTD induced by the selective agonist (RS)-3,5-dihydroxyphenylglycine (DHPG-LTD) was inhibited by previous preconditioning brief high-frequency stimulation (HFS), regardless of whether the preconditioning HFS induced long-term potentiation. Blockade of NMDA receptors during the preconditioning HFS did not alter the inhibition of DHPG-LTD by the HFS. However, antagonism of mGluRs during the preconditioning HFS did prevent the inhibition of DHPG-LTD by the HFS. In addition, blocking PKC stimulation during the preconditioning HFS also prevented the inhibitory effect of HFS on DHPG-LTD. The DHPG-LTD itself was not inhibited by blocking PKC stimulation but was inhibited by blocking the p38 mitogen-activated protein kinase (MAPK) pathway. Thus, whereas the DHPG-LTD is mediated via activation of the p38 MAPK pathway, the inhibitory effects of preconditioning HFS on DHPG-LTD are mediated via stimulation of group I/II mGluRs, activation of PKC, and subsequent blocking of the functioning of group I mGluR.