Enduring Changes in Neuronal Function upon Systemic Inflammation Are NLRP3 Inflammasome Dependent.

Neuroinflammation can be caused by various insults to the brain and represents an important pathologic hallmark of neurodegenerative diseases including Alzheimer's disease (AD). Infection-triggered acute systemic inflammation is able to induce neuroinflammation and may negatively affect neuronal morphology, synaptic plasticity, and cognitive function. In contrast to acute effects, persisting consequences for the brain on systemic immune stimulation remain largely unexplored. Here, we report an age-dependent vulnerability of wild-type (WT) mice of either sex toward a systemic immune stimulation by Salmonella typhimurium lipopolysaccharide (LPS). Decreased neuronal complexity three months after peripheral immune stimulation is accompanied by impairment in long-term potentiation (LTP) and spatial learning. Aged APP/PS1 mice reveal an increased sensitivity also to LPS of Escherichia coli, which had no effect in WT mice. We further report that these effects are mediated by NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation, since the genetic ablation and pharmacological inhibition using the NLRP3 inhibitor MCC950 rescue the morphological and electrophysiological phenotype.SIGNIFICANCE STATEMENT Acute peripheral immune stimulation has been shown to have both positive and negative effects on Aß deposition. Improvements or worsening may be possible in acute inflammation. However, there is still no evidence of effects longer than a month after stimulation. The data are pointing to an important role of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome for mediating the long-term consequences of systemic immune stimulation, which in addition turns out to be age dependent.

Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease.

Our knowledge on the plastic functions of the serotonin (5-HT) receptor subtype 7 (5-HT7R) in the brain physiology and pathology have advanced considerably in recent years. A wealth of data show that 5-HT7R is a key player in the establishment and remodeling of neuronal cytoarchitecture during development and in the mature brain, and its dysfunction is linked to neuropsychiatric and neurodevelopmental diseases. The involvement of this receptor in synaptic plasticity is further demonstrated by data showing that its activation allows the rescue of long-term potentiation (LTP) and long-term depression (LTD) deficits in various animal models of neurodevelopmental diseases. In addition, it is becoming clear that the 5-HT7R is involved in inflammatory intestinal diseases, modulates the function of immune cells, and is likely to play a role in the gut-brain axis. In this review, we will mainly focus on recent findings on this receptor's role in the structural and synaptic plasticity of the mammalian brain, although we will also illustrate novel aspects highlighted in gastrointestinal (GI) tract and immune system.

Disturbance of Metabotropic Glutamate Receptor-Mediated Long-Term Depression (mGlu-LTD) of Excitatory Synaptic Transmission in the Rat Hippocampus After Prenatal Immune Challenge.

Maternal immune challenge has proved to induce moderate to severe behavioral disabilities in the offspring. Cognitive/behavioral deficits are supported by changes in synaptic plasticity in different brain areas. We have reported previously that prenatal exposure to bacterial LPS could induce inhibition of hippocampal long-term potentiation (LTP) in the CA1 area of the juvenile/adult male offspring associated with spatial learning inabilities. Nevertheless, deficits in plasticity could be observed at earlier stages as shown by the early loss of long-term depression (LTD) in immature animals. Moreover, aberrant forms of plasticity were also evidenced such as the transient occurrence of LTP instead of LTD in 15-25 day-old animals. This switch from LTD to LTP seemed to involve the activation of metabotropic glutamate receptor subtype 1 and 5 (mGlu1/5). We have thus investigated here whether the long-term depression elicited by the direct activation of these receptors (mGlu-LTD) with a selective agonist was also disturbed after prenatal stress. We find that in prenatally stressed rats, mGlu1/5 stimulation elicits long-term potentiation (mGlu-LTP) independently of N-methyl-D-aspartate receptors. Both mGlu5 and mGlu1 receptors are involved in this switch of plasticity. Moreover, this mGlu-LTP is still observed at later developmental stages than previously reported, i.e. after 25 day-old. In addition, increasing synaptic GABA with tiagabine tends to inhibit mGlu-LTP occurrence. By contrast, long-term depression induced with the activation of CB1 cannabinoid receptor is unaffected by prenatal stress. Therefore, prenatal stress drastically alters mGlu1/5-associated plasticity throughout development. MGlu-mediated plasticity is an interesting parameter to probe the long-lasting deficits reported in this model.

Molecular Mechanisms of Early and Late LTP.

LTP is the most intensively studied cellular model of the memory and generally divided at least two distinct phases as early and late. E-LTP requires activation of CaMKII that initiates biochemical events and trafficking of proteins, which eventually potentiate synaptic transmission, and is independent of de novo protein synthesis. In contrast, L-LTP requires gene expression and local protein synthesis regulated via TrkB receptor- and functional prions CPEB2-3-mediated translation. Maintenance of LTP for longer periods depends on constitutively active PKMζ. Throughout this review, current knowledge about early and late phases of LTP will be reviewed.

The voltage-gated potassium channel Kv1.3 is required for microglial pro-inflammatory activation in vivo.

Microglia show a rich repertoire of activation patterns regulated by a complex ensemble of surface ion channels, receptors, and transporters. We and others have investigated whether microglia vary their K+ channel expression as a means to achieve functional diversity. However, most of the prior studies were conducted using in vitro models such as BV2 cells, primary microglia, or brain slices in culture, which may not accurately reflect microglia physiology in adult individuals. Here we employed an in vivo mouse model of selective innate immune activation by intracerebroventricular injection of lipopolysaccharides (ICV-LPS) to determine the role of the voltage-gated Kv1.3 channel in LPS-induced M1-like microglial activation. Using microglia acutely isolated from adult brains, we detected Kv1.3 and Kir2.1 currents, and found that ICV-LPS increased the current density and RNA expression of Kv1.3 but did not affect those of Kir2.1. Genetic knockout of Kv1.3 abolished LPS-induced microglial activation exemplified by Iba-1 immunoreactivity and expression of pro-inflammatory mediators such as IL-1ß, TNF-α, IL-6, and iNOS. Moreover, Kv1.3 knockout mitigated the LPS-induced impairment of hippocampal long-term potentiation (hLTP), suggesting that Kv1.3 activity regulates pro-inflammatory microglial neurotoxicity. Pharmacological intervention using PAP-1, a small molecule that selectively blocks homotetrameric Kv1.3 channels, achieved anti-inflammatory and hLTP-recovery effects similar to Kv1.3 knockout. We conclude that Kv1.3 is required for microglial M1-like pro-inflammatory activation in vivo. A significant implication of our in vivo data is that Kv1.3 blockers could be therapeutic candidates for neurological diseases where microglia-mediated neurotoxicity is implicated in the pathogenesis.

Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients.

The identification of circulating autoantibodies against neuronal receptors in neuropsychiatric disorders has fostered new conceptual and clinical frameworks. However, detection reliability, putative presence in different diseases and in health have raised questions about potential pathogenic mechanism mediated by autoantibodies. Using a combination of single molecule-based imaging approaches, we here ascertain the presence of circulating autoantibodies against glutamate NMDA receptor (NMDAR-Ab) in about 20% of psychotic patients diagnosed with schizophrenia and very few healthy subjects. NMDAR-Ab from patients and healthy subjects do not compete for binding on native receptor. Strikingly, NMDAR-Ab from patients, but not from healthy subjects, specifically alter the surface dynamics and nanoscale organization of synaptic NMDAR and its anchoring partner the EphrinB2 receptor in heterologous cells, cultured neurons and in mouse brain. Functionally, only patients' NMDAR-Ab prevent long-term potentiation at glutamatergic synapses, while leaving NMDAR-mediated calcium influx intact. We unveil that NMDAR-Ab from psychotic patients alter NMDAR synaptic transmission, supporting a pathogenically relevant role.

A cytokine network involving brain-borne IL-1ß, IL-1ra, IL-18, IL-6, and TNFα operates during long-term potentiation and learning.

We have previously shown that long-term potentiation (LTP) induces hippocampal IL-1ß and IL-6 over-expression, and interfering their signalling either inhibits or supports, respectively, LTP maintenance. Consistently, blockade of endogenous IL-1 or IL-6 restricts or favours hippocampal-dependent memory, effects that were confirmed in genetically manipulated mice. Since cytokines are known for their high degree of mutual crosstalk, here we studied whether a network of cytokines with known neuromodulatory actions is activated during LTP and learning. We found that, besides IL-1ß and IL-6, also IL-1 receptor antagonist (IL-1ra) and IL-18, but not TNFα are over-expressed during LTP maintenance in freely moving rats. The increased expression of these cytokines is causally related to an increase in synaptic strength since it was abrogated when LTP was interfered by blockade of NMDA-glutamate receptors. Likewise, IL-1 and IL-6 were found to be over-expressed in defined regions of the hippocampus during learning a hippocampus-dependent task. However, during learning, changes in IL-18 were restricted to the dorsal hippocampus, and no differences in TNFα and IL1-ra expression were noticed in the hippocampus. Noticeably, IL-1ra transcripts were significantly reduced in the prefrontal cortex. The relation between cytokine expression and learning was causal because such changes were not observed in animals from a pseudo-trained group that was subject to the same manipulation but could not learn the task. Taken together with previous studies, we conclude that activation of a cytokine network in the brain is a physiologic relevant phenomenon not only for LTP maintenance but also for certain types of learning.

Systemic LPS induces spinal inflammatory gene expression and impairs phrenic long-term facilitation following acute intermittent hypoxia.

Although systemic inflammation occurs in most pathological conditions that challenge the neural control of breathing, little is known concerning the impact of inflammation on respiratory motor plasticity. Here, we tested the hypothesis that low-grade systemic inflammation induced by lipopolysaccharide (LPS, 100 µg/kg ip; 3 and 24 h postinjection) elicits spinal inflammatory gene expression and attenuates a form of spinal, respiratory motor plasticity: phrenic long-term facilitation (pLTF) induced by acute intermittent hypoxia (AIH; 3, 5 min hypoxic episodes, 5 min intervals). pLTF was abolished 3 h (vehicle control: 67.1 ± 27.9% baseline; LPS: 3.7 ± 4.2%) and 24 h post-LPS injection (vehicle: 58.3 ± 17.1% baseline; LPS: 3.5 ± 4.3%). Pretreatment with the nonsteroidal anti-inflammatory drug ketoprofen (12.5 mg/kg ip) restored pLTF 24 h post-LPS (55.1 ± 12.3%). LPS increased inflammatory gene expression in the spleen and cervical spinal cord (homogenates and isolated microglia) 3 h postinjection; however, all molecules assessed had returned to baseline by 24 h postinjection. At 3 h post-LPS, cervical spinal iNOS and COX-2 mRNA were differentially increased in microglia and homogenates, suggesting differential contributions from spinal cells. Thus LPS-induced systemic inflammation impairs AIH-induced pLTF, even after measured inflammatory genes returned to normal. Since ketoprofen restores pLTF even without detectable inflammatory gene expression, "downstream" inflammatory molecules most likely impair pLTF. These findings have important implications for many disease states where acute systemic inflammation may undermine the capacity for compensatory respiratory plasticity.

Synaptic correlates of increased cognitive vulnerability with aging: peripheral immune challenge and aging interact to disrupt theta-burst late-phase long-term potentiation in hippocampal area CA1.

Variability in cognitive functioning increases markedly with age, as does cognitive vulnerability to physiological and psychological challenges. Exploring the basis of this vulnerability may provide important insights into the mechanisms underlying aging-associated cognitive decline. As we have previously reported, the cognitive abilities of aging (24-month-old) F344 x BN rats are generally good, but are more vulnerable to the consequences of a peripheral immune challenge (an intraperitoneal injection of live Escherichia coli) than those of their younger (3-month-old) counterparts. Four days after the injection, the aging, but not the young rats show profound memory deficits, specific to the consolidation of hippocampus-dependent memory processes. Here, we have extended these observations, using hippocampal slices to examine for the first time the combined effects of aging and a recent infection on several forms of synaptic plasticity. We have found that the specific deficit in long-lasting memory observed in the aged animals after infection is mirrored by a specific deficit in a form of long-lasting synaptic plasticity. The late-phase long-term potentiation induced in area CA1 using theta-burst stimulation is particularly compromised by the combined effects of aging and infection-a deficit that can be ameliorated by intra-cisterna magna administration of the naturally occurring antiinflammatory cytokine IL-1Ra (interleukin-1 receptor antagonist). These data support the idea that the combination of aging and a negative life event such as an infection might produce selective, early-stage failures of synaptic plasticity in the hippocampus, with corresponding selective deficits in memory.

LTP impairment by fractalkine/CX3CL1 in mouse hippocampus is mediated through the activity of adenosine receptor type 3 (A3R).

We have examined how the chemokine fractalkine/CX(3)CL1 influences long-term potentiation (LTP) in CA1 mouse hippocampal slices. Field potentials (fEPSPs) were recorded upon electrical stimulation of Schaffer collaterals. It was found that application of CX(3)CL1 inhibits LTP when present during the critical induction period. LTP impairment (i) failed to occur in CX(3)CR1 deficient mice (CX(3)CR1(GFP/GFP)) and in the presence of okadaic acid (OA); (ii) required the activation of adenosine receptor 3 (A(3)R), since it was prevented in A(3)R-deficient mice or by MRS1523, a selective A(3)R antagonist. Together, these findings indicate that CX(3)CL1 inhibits hippocampal LTP through A(3)R activity.

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.

Lipopolysaccharide impairs long-term potentiation and recognition memory and increases p75NTR expression in the rat dentate gyrus.

The role of the neurotrophins, including nerve growth factor, in synaptic plasticity is well established. These proteins exert their effects via activation of Trk receptor tyrosine kinases and the p75 neurotrophin receptor (p75NTR). While Trk receptor activation is associated with functions such as cell survival, learning and enhancement of synaptic transmission, p75NTR can modulate long-term depression and has been reported to be a regulator of apoptosis. Peripheral administration of lipopolysaccharide (LPS) has been shown to exert a number of effects centrally, including inhibition of hippocampal synaptic plasticity. Here we report that LPS induces a blockade of long-term potentiation and recognition memory that is concomitant with increased expression of the p75NTR in dentate gyrus. In addition, LPS blocks plasticity-associated changes in nerve growth factor expression, TrkA activation and extracellular signal-regulated kinase activation. These data are consistent with the hypothesis that synaptic plasticity in the dentate gyrus is associated with changes in neurotrophin signaling and that the inhibition of these plastic changes by LPS may be due in part to its ability to impact on these signaling cascades.

Lipopolysaccharide-induced increase in signalling in hippocampus is abrogated by IL-10--a role for IL-1 beta?

Parenterally administered lipopolysaccharide (LPS) increases the concentration of the pro-inflammatory cytokine interleukin-1beta (IL-1beta) in the rat hippocampus and evidence suggests that this effect plays a significant role in inhibiting long-term potentiation (LTP). The anti-inflammatory cytokine IL-10, antagonizes certain effects of IL-1beta, so if the effects of LPS are mediated through an increase in IL-1beta, it might be predicted that IL-10 would also abrogate the effect of LPS. Here, we report that IL-10 reversed the inhibitory effect of LPS on LTP and the data couple this with an inhibitory effect on the LPS-induced increase in IL-1beta. LPS treatment increased hippocampal expression of IL-1 receptor Type I protein. Consistent with the LPS-induced increases in IL-1beta concentration and receptor expression, were downstream changes which included enhanced phosphorylation of IRAK and the stress-activated kinases, JNK and p38; these LPS-induced changes were reversed by IL-10, which concurs with the idea that these events are triggered by increased activation of IL-1RI by IL-1beta. We provide evidence which indicates that LPS treatment leads to evidence of cell death and this was reversed in hippocampus prepared from LPS-treated rats which received IL-10. The evidence is therefore consistent with the idea that IL-10 acts to protect neuronal tissue from the detrimental effects induced by LPS.

A dual role for interleukin-1 in LTP in mouse hippocampal slices.

Interleukin-1 (IL-1) exerts numerous effects in the central nervous system and has been implicated in synaptic plasticity. The objective of this study was to investigate the role of endogenous as well as exogenous IL-1 on long-term potentiation (LTP). Hippocampal slices incubated at 34-36 degrees C show enhanced levels of IL-1alpha and IL-1beta compared to slices incubated at 21-24 degrees C. IL-1 inhibits LTP induced by theta-burst stimulation (TBS) at either temperature. IL-1 receptor antagonist (IL-1ra) had no effect on LTP at 21-24 degrees C, but displayed a concentration-dependent inhibition of LTP at 34-36 degrees C. Under control conditions, the magnitude of LTP was not temperature dependent. These data suggest that IL-1 is required for LTP under physiological conditions but at higher doses, as encountered in pathological conditions, IL-1 inhibits LTP.

Attenuation of LPS-induced changes in synaptic activity in rat hippocampus by Vasogen's Immune Modulation Therapy.

Systemic injection of lipopolysaccharide (LPS) blocks the expression of long-term potentiation in the hippocampus of the rat. This is coupled with increased IL-1beta concentration and c-Jun NH(2)-terminal kinase activity, as well as an increase in the number of cells displaying apoptotic characteristics in the hippocampus. Vasogen's Immune Modulation Therapy (IMT) is a procedure involving intramuscular administration of syngeneic blood which has been exposed ex vivo to elevated temperature, oxidation and ultraviolet light. We report that Vasogen's IMT significantly abrogates these LPS-induced effects with a concomitant increase in the concentration of the anti-inflammatory cytokine IL-10. These data suggest that Vasogen's IMT may play a protective role against the deleterious effects of immune insults in the brain.

Antigen-induced synaptic plasticity in sympathetic ganglia from actively and passively sensitized guinea-pigs.

Alterations in synaptic efficacy induced by antigen challenge to isolated superior cervical ganglia (SCG) were monitored by measuring the magnitude of the postganglionic compound action potential (CAP) elicited by electrical stimulation of the cervical sympathetic nerve trunk. Antigen-induced changes in the CAP were measured in SCG removed from actively and from passively sensitized guinea-pigs. Additionally, some SCG were sensitized in vitro by incubating naive ganglia 24 h in serum obtained from actively sensitized animals. Histamine released from SCG upon specific antigenic challenge was measured to assess the effectiveness of the two forms of sensitization. Challenging SCG isolated from passively or actively sensitized animals with the sensitizing antigen, ovalbumin (OVA), produced a sustained potentiation of the CAP lasting longer than 30 min (antigen-induced long-term potentiation, A-LTP) and a net increase in histamine release. Neither the magnitude nor duration of A-LTP induced by passive sensitization differed significantly (p < 0.05) from results after active sensitization. The existence of A-LTP in SCG following passive sensitization indicates that the afferent limb of the immune system is not required for the development of this phenomenon and that the immune cells and the mediators responsible for A-LTP are resident to sympathetic ganglia.

[The effect of monoclonal antibodies on evoked potentials and on the development of long-term posttetanic potentiation of the hippocampus]. / Vliianie monoklonal'nykh antitel na vyzvannye potentsialy i razvitie dlitel'noi posttetanicheskoi potentsiatsii gippokampa.

A panel of hybridoma clones producing monoclonal antibodies (Mabs) to the antigens of synaptosomes from rat brain cortex was generated. In immunocytochemical experiments 5F5-B6 Mabs stained stratum moleculare in hippocampus and cerebellum of adult rats intraventricular introduction of 5F5-B6 Mabs was shown to block LTP formation in fascia dentata and to change the evoked potential and population spike amplitude.