Behavioral and pathological outcomes in MOG 35-55 experimental autoimmune encephalomyelitis

We measured inflammatory and neural markers of disease from 7 days to one year after induction of experimental autoimmune encephalomyelitis (EAE) by immunization with myelin oligodendrocyte glycoprotein (MOG) peptide. Axon loss began before behavioral signs when T cell infiltration and microglial activation were very subtle. Remyelination was only detectable ultrastructurally. Axon numbers in the dorsal column plateau around day 30 p.i. while behavioral measures (EAE scores, rotarod, grip strength) partially recover. These results provide a starting point for testing potential neuroprotective treatments for multiple sclerosis (MS).     

Maternal immune activation alters visual acuity and retinogeniculate axon pruning in offspring mice

Individuals with autism spectrum disorder (ASD) have been found to have a variety of sensory processing deficits. Here we report that maternal immune activation, a known factor for ASD, alters visual acuity in the offspring mice. By intraperitoneally injecting polyinosinic-polycytidylic acid (polyI:C) to induce maternal immune activation during embryonic days 10 to 14, we found that polyI:C treatment impairs visual acuity in young adult offspring mice as examined by their optomotor responses. Concurrently, polyI:C treatment suppresses retinogeniculate axon elimination, resulting in a high fraction of weak optical fibers innervating the relay neurons in the visual thalamus. The results link in-utero maternal inflammation to defective optical fiber pruning and arrested developmental strengthening of single optic fibers which may underlie impaired visual acuity.     

Chronic mechanical hypersensitivity in experimental autoimmune encephalomyelitis is regulated by disease severity and neuroinflammation

Chronic pain severely affects quality of life in more than half of people living with multiple sclerosis (MS). A commonly-used model of MS, experimental autoimmune encephalomyelitis (EAE), typically presents with hindlimb paralysis, neuroinflammation and neurodegeneration. However, this paralysis may hinder the use of pain behavior tests, with no apparent hypersensitivity observed post-peak disease. We sought to adapt the classic actively-induced EAE model to optimize its pain phenotype. EAE was induced with MOG_35-55/CFA and 100–600 ng pertussis toxin (PTX), and mice were assessed for mechanical, cold and thermal sensitivity over a 28-day period. Spinal cord tissue was collected at 14 and 28 days post-injection to assess demyelination and neuroinflammation. Only mice treated with 100 ng PTX exhibited mechanical hypersensitivity. Hallmarks of disease pathology, including demyelination, immune cell recruitment, cytokine expression, glial activation, and neuronal damage were higher in EAE mice induced with moderate (200 ng) doses of pertussis toxin, compared to those treated with low (100 ng) levels. Immunostaining demonstrated activated astrocytes and myeloid/microglial cells in both EAE groups. These results indicate that a lower severity of EAE disease may allow for the study of pain behaviors while still presenting with disease pathology. By using this modified model, researchers may better study the mechanisms underlying pain.     

Additive effects of maternal iron deficiency and prenatal immune activation on adult behaviors in rat offspring

Both iron deficiency (ID) and infection are common during pregnancy and studies have described altered brain development in offspring as a result of these individual maternal exposures. Given their high global incidence, these two insults may occur simultaneously during pregnancy. We recently described a rat model which pairs dietary ID during pregnancy and prenatal immune activation. Pregnant rats were placed on iron sufficient (IS) or ID diets from embryonic day 2 (E2) until postnatal day 7, and administered the bacterial endotoxin, lipopolysaccharide (LPS) or saline on E15/16. In this model, LPS administration on E15 caused greater induction of the pro-inflammatory cytokines, interleukin-6 and tumor necrosis factor-α, in ID dams compared to IS dams. This suggested that the combination of prenatal immune activation on a background of maternal ID might have more adverse neurodevelopmental consequences for the offspring than exposure to either insult alone. In this study we used this model to determine whether combined exposure to maternal ID and prenatal immune activation interact to affect juvenile and adult behaviors in the offspring. We assessed behaviors relevant to deficits in humans or animals that have been associated with exposure to either maternal ID or prenatal immune activation alone. Adult offspring from ID dams displayed significant deficits in pre-pulse inhibition of acoustic startle and in passive avoidance learning, together with increases in cytochrome oxidase immunohistochemistry, a marker of metabolic activity, in the ventral hippocampus immediately after passive avoidance testing. Offspring from LPS treated dams showed a significant increase in social behavior with unfamiliar rats, and subtle locomotor changes during exploration in an open field and in response to amphetamine. Surprisingly, there was no interaction between effects of the two insults on the behaviors assessed, and few observed alterations in juvenile behavior. Our findings show that long-term effects of maternal ID and prenatal LPS were additive, such that offspring exposed to both insults displayed more adult behavioral abnormalities than offspring exposed to one alone.     

Maternal immune activation primes deficiencies in adult hippocampal neurogenesis

Neurogenesis, the process in which new neurons are generated, occurs throughout life in the mammalian hippocampus. Decreased adult hippocampal neurogenesis (AHN) is a common feature across psychiatric disorders, including schizophrenia, depression- and anxiety-related behaviours, and is highly regulated by environmental influences. Epidemiological studies have consistently implicated maternal immune activation (MIA) during neurodevelopment as a risk factor for psychiatric disorders in adulthood. The extent to which the reduction of hippocampal neurogenesis in adulthood may be driven by early life exposures, such as MIA, is however unclear. We therefore reviewed the literature for evidence of the involvement of MIA in disrupting AHN. Consistent with our hypothesis, data from both in vivo murine and in vitro human models of AHN provide evidence for key roles of specific cytokines induced by MIA in the foetal brain in disrupting hippocampal neural progenitor cell proliferation and differentiation early in development. The precise molecular mechanisms however remain unclear. Nonetheless, these data suggest a potential latent vulnerability mechanism, whereby MIA primes dysfunction in the unique hippocampal pool of neural stem/progenitor cells. This renders offspring potentially more susceptible to additional environmental exposures later in life, such as chronic stress, resulting in the unmasking of psychopathology. We highlight the need for studies to test this hypothesis using validated animal models of MIA, but also to test the relevance of such data for human pathology at a molecular basis through the use of patient-derived induced pluripotent stem cells (hiPSC) differentiated into hippocampal progenitor cells.     

Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring

Maternal exposure to viral infection has been associated with an increased risk of schizophrenia in the offspring, and it has been suggested that the maternal immune response may interfere with normal fetal brain development. Although studies in rodents have shown that perinatal viral infections can lead to neuropathological and behavioral abnormalities considered relevant to schizophrenia, it is not clear whether these consequences are due to the infection itself or to the maternal immune response to infection. We show that an induction of maternal immune stimulation without exposure to a virus by injecting pregnant dams with the synthetic cytokine releaser polyriboinosinic-polyribocytidilic acid (poly I:C) leads to abnormal behavioral and pharmacological responses in the adult offspring. As in schizophrenia, these offspring displayed excessive behavioral switching, manifested in the loss of latent inhibition and in rapid reversal learning. Consistent with the clinical pharmacology of schizophrenia, both deficits were alleviated by antipsychotic treatment. In addition, these offspring displayed increased sensitivity to the locomotor-stimulating effects of MK-801, pointing to developmental alterations of the dopaminergic and/or glutamatergic systems. Prenatal poly I:C administration did not produce learning deficits in classical fear conditioning, active avoidance, discrimination learning and water maze. These results show that the maternal immune response is sufficient to cause behavioral and pharmacological alterations relevant to schizophrenia in the adult offspring.     

Maternal allergic inflammation in rats impacts the offspring perinatal neuroimmune milieu and the development of social play,locomotor behavior,and cognitive flexibility

Maternal systemic inflammation increases risk for neurodevelopmental disorders like autism, ADHD, and schizophrenia in offspring. Notably, these disorders are male-biased. Studies have implicated immune system dysfunction in the etiology of these disorders, and rodent models of maternal immune activation provide useful tools to examine mechanisms of sex-dependent effects on brain development, immunity, and behavior. Here, we employed an allergen-induced model of maternal inflammation in rats to characterize levels of mast cells and microglia in the perinatal period in male and female offspring, as well as social, emotional, and cognitive behaviors throughout the lifespan. Adult female rats were sensitized to ovalbumin (OVA), bred, and challenged intranasally on gestational day 15 of pregnancy with OVA or saline. Allergic inflammation upregulated microglia in the fetal brain, increased mast cell number in the hippocampus on the day of birth, and conferred region-, time- and sex- specific changes in microglia measures. Additionally, offspring of OVA-exposed mothers subsequently exhibited abnormal social behavior, hyperlocomotion, and reduced cognitive flexibility. These data demonstrate the long-term effects of maternal allergic challenge on offspring development and provide a basis for understanding neurodevelopmental disorders linked to maternal systemic inflammation in humans.     

Male rats develop more severe experimental autoimmune encephalomyelitis than female rats: Sexual dimorphism and diergism at the spinal cord level

Compared with females, male Dark Agouti (DA) rats immunized for experimental autoimmune encephalomyelitis (EAE) with rat spinal cord homogenate in complete Freund’s adjuvant (CFA) exhibited lower incidence of the disease, but the maximal neurological deficit was greater in the animals that developed the disease. Consistently, at the peak of the disease greater number of reactivated CD4+CD134+CD45RC− T lymphocytes was retrieved from male rat spinal cord. Their microglia/macrophages were more activated and produced greater amount of prototypic proinflammatory cytokines in vitro. Additionally, oppositely to the expression of mRNAs for IL-12/p35, IL-10 and IL-27/p28, the expression of mRNA for IL-23/p19 was upregulated in male rat spinal cord mononuclear cells. Consequently, the IL-17+:IFN-γ+ cell ratio within T lymphocytes from their spinal cord was skewed towards IL-17+ cells. Within this subpopulation, the IL-17+IFN-γ+:IL-17+IL-10+ cell ratio was shifted towards IL-17+IFN-γ+ cells, which have prominent tissue damaging capacity. This was associated with an upregulated expression of mRNAs for IL-1β and IL-6, but downregulated TGF-β mRNA expression in male rat spinal cord mononuclear cells. The enhanced GM-CSF mRNA expression in these cells supported the greater pathogenicity of IL-17+ T lymphocytes infiltrating male spinal cord. In the inductive phase of the disease, contrary to the draining lymph node, in the spinal cord the frequency of CD134+ cells among CD4+ T lymphocytes and the frequency of IL-17+ cells among T lymphocytes were greater in male than in female rats. This most likely reflected an enhanced transmigration of mononuclear cells into the spinal cord (judging by the lesser spinal cord CXCL12 mRNA expression), the greater frequency of activated microglia/macrophages and the increased expression of mRNAs for Th17 polarizing cytokines in male rat spinal cord mononuclear cells. Collectively, the results showed cellular and molecular mechanisms underlying the target organ specific sexual dimorphism in the T lymphocyte-dependent immune/inflammatory response, and suggested a substantial role for the target organ in shaping the sexually dimorphic clinical outcome of EAE.     

Astrocytes are the major intracerebral source of macrophage inflammatory protein-3alpha/CCL20 in relapsing experimental autoimmune encephalomyelitis and in vitro

Macrophage inflammatory protein-3alpha/CCL20 is a recently identified chemokine that binds to CCR6 and acts as a chemoattractant for memory/differentiated T-cells, B-cells, and immature dendritic cells. We have previously reported that CCL20 and CCR6 mRNAs are expressed in the CNS of SJL mice with experimental autoimmune encephalomyelitis (EAE) and that CCL20 is produced by CNS-infiltrating leukocytes at disease onset and, additionally, by intraparenchymal astrocyte-like cells during disease relapses. In this study, we provide further immunohistochemical evidence that astrocytes represent the main CNS source of CCL20 during EAE. Moreover, we show that the proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha, but not interferon-gamma, induce expression of CCL20 mRNA and secretion of CCL20 protein in cultures of mouse brain-derived astrocytes. We also show that supernatants from cytokine-activated astrocytes stimulate the migration of polarized T helper cells and that this effect is partially inhibited by anti-CCL20 antibody. These findings suggest that, through secretion of CCL20, astrocytes could play an important role in orchestrating the recruitment of specific leukocyte subsets to the inflamed CNS and in regulating CNS-targeted immune responses.     

Characterization of relapsing–remitting and chronic forms of experimental autoimmune encephalomyelitis in C57BL/6 mice

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system (CNS). Like MS, the animal model experimental autoimmune encephalomyelitis (EAE) is characterized by CNS inflammation and demyelination and can follow a relapsing–remitting (RR) or chronic (CH) disease course. The molecular and pathological differences that underlie these different forms of EAE are not fully understood. We have compared the differences in RR‐ and CH‐EAE generated in the same mouse strain (C57BL/6) using the same antigen. At the peak of disease when mice in both groups have similar clinical scores, CH‐EAE is associated with increased lesion burden, myelin loss, axonal damage, and chemokine/cytokine expression when compared with RR‐EAE. We further showed that inflammation and myelin loss continue to worsen in later stages of CH‐EAE, whereas these features are largely resolved at the equivalent stage in RR‐EAE. Additionally, axonal loss at these later stages is more severe in CH‐EAE than in RR‐EAE. We also demonstrated that CH‐EAE is associated with a greater predominance of CD8⁺ T cells in the CNS that exhibit MOG_35–55 antigen specificity. These studies therefore showed that, as early as the peak stage of disease, RR‐ and CH‐EAE differ remarkably in their immune cell profile, chemokine/cytokine responses, and histopathological features. These data also indicated that this model of CH‐EAE exhibits pathological features of a chronic‐progressive disease profile and suggested that the sustained chronic phenotype is due to a combination of axonal loss, myelin loss, and continuing inflammation. © 2009 Wiley‐Liss, Inc.     

Maternal immune activation altered microglial immunoreactivity in the brain of postnatal day 2 rat offspring

Microglia, the resident immune cells of the central nervous system, play critical roles in neurodevelopment, synaptic pruning, and neuronal wiring. Early in development, microglia migrate via the tangential and radial migration pathways to their final destinations and mature gradually, a process that includes morphological changes. Recent research has implicated microglial abnormality in the etiology of schizophrenia. Since prenatal exposure to viral or bacterial infections due to maternal immune activation (MIA) leads to increased risk of schizophrenia in the offspring during adulthood, the present study systematically investigated how MIA induced by polyinosinic:polycytidylic acid (a mimic of viral double‐stranded RNA) affected microglial immunoreactivity along the migration and maturation trajectories in the brains of male and female rat offspring on postnatal day (PND) 2. The immunohistochemistry revealed significant changes in the density of IBA‐1 immunoreactive cells in the corpus callosum, somatosensory cortex, striatum, and the subregions of the hippocampus of the MIA offspring. The male and female MIA offspring displayed markedly altered microglial immunoreactivity in both the tangential and radial migration, as well as maturation, pathways when compared to their sex‐ and age‐matched controls as evidenced by morphology‐based cell counting. Given the important roles of microglia in synaptic pruning and neuronal wiring and survival, these changes may lead to structural and functional neurodevelopmental abnormalities, and so contribute to the functional deficits observed in juvenile and adult MIA offspring. Future research is required to systematically determine how MIA affects microglial migration and maturation in rat offspring.     

The interaction between maternal immune activation and alpha 7 nicotinic acetylcholine receptor in regulating behaviors in the offspring

Mutation of human chromosome 15q13.3 increases the risk for autism and schizophrenia. One of the noteworthy genes in 15q13.3 is CHRNA7, which encodes the nicotinic acetylcholine receptor alpha 7 subunit (α7nAChR) associated with schizophrenia in clinical studies and rodent models. This study investigates the role of α7nAChR in maternal immune activation (MIA) mice model, a murine model of environmental risk factor for autism and schizophrenia. We provided choline, a selective α7nAChR agonist among its several developmental roles, in the diet of C57BL/6N wild-type dams throughout the gestation and lactation period and induced MIA at mid-gestation. The adult offspring behavior and gene expression profile in the maternal-placental-fetal axis at mid-gestation were investigated. We found that choline supplementation prevented several MIA-induced behavioral abnormalities in the wild-type offspring. Pro-inflammatory cytokine interleukin-6 (Il6) and Chrna7 gene expression in the wild-type fetal brain were elevated by poly(I:C) injection and were suppressed by gestational choline supplementation. We further investigated the gene expression level of Il6 in Chrna7 mutant mice. We found that the basal level of Il6 was higher in Chrna7 mutant fetal brain, which suggests that α7nAChR may serve an anti-inflammatory role in the fetal brain during development. Lastly, we induced MIA in Chrna7^+/− offspring. The Chrna7^+/− offspring were more vulnerable to MIA, with increased behavioral abnormalities. Our study shows that α7nAChR modulates inflammatory response affecting the fetal brain and demonstrates its effects on offspring behavior development after MIA.     

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

Prenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorder in later life, including schizophrenia, bipolar disorder, and autism. These brain disorders are also characterized by pre- and postsynaptic deficits. Using a well-established mouse model of maternal exposure to the viral mimetic polyriboinosinic–polyribocytidilic acid [poly(I:C)], we examined whether prenatal immune activation might cause synaptic deficits in the hippocampal formation of pubescent and adult offspring. Based on the widely appreciated role of microglia in synaptic pruning, we further explored possible associations between synaptic deficits and microglia anomalies in offspring of poly(I:C)-exposed and control mothers. We found that prenatal immune activation induced an adult onset of presynaptic hippocampal deficits (as evaluated by synaptophysin and bassoon density). The early-life insult further caused postsynaptic hippocampal deficits in pubescence (as evaluated by PSD95 and SynGAP density), some of which persisted into adulthood. In contrast, prenatal immune activation did not change microglia (or astrocyte) density, nor did it alter their activation phenotypes. The prenatal manipulation did also not cause signs of persistent systemic inflammation. Despite the absence of overt glial anomalies or systemic inflammation, adult offspring exposed to prenatal immune activation displayed increased hippocampal IL-1β levels. Taken together, our findings demonstrate that age-dependent synaptic deficits and abnormal pro-inflammatory cytokine expression can occur during postnatal brain maturation in the absence of microglial anomalies or systemic inflammation.     

Lipopolysaccharide-induced maternal immune activation modulates microglial CX3CR1 protein expression and morphological phenotype in the hippocampus and dentate gyrus,resulting in cognitive inflexibility during late adolescence

Inflammation during pregnancy can disturb brain development and lead to disorders in the progeny, including autism spectrum disorder and schizophrenia. However, the mechanism by which a prenatal, short-lived increase of cytokines results in adverse neurodevelopmental outcomes remains largely unknown. Microglia—the brain’s resident immune-cells—stand as fundamental cellular mediators, being highly sensitive and responsive to immune signals, which also play key roles during normal development.The fractalkine signaling axis is a neuron-microglia communication mechanism used to regulate neurogenesis and network formation. Previously, we showed hippocampal reduction of fractalkine receptor (Cx3cr1) mRNA at postnatal day (P) 15 in male offspring exposed to maternal immune activation induced with lipopolysaccharide (LPS) during late gestation, which was concomitant to an increased dendritic spine density in the dentate gyrus, a neurogenic niche. The current study sought to evaluate the origin and impact of this reduced hippocampal Cx3cr1 mRNA expression on microglia and cognition. We found that microglial total cell number and density are not affected in the dorsal hippocampus and dentate gyrus, respectively, but that the microglial CX3CR1 protein is decreased in the hippocampus of LPS-male offspring at P15. Further characterization of microglial morphology in the dentate gyrus identified a more ameboid phenotype in LPS-exposed offspring, predominantly in males, at P15. We thus explored maternal plasma and fetal brain cytokines to understand the mechanism behind microglial priming, showing a robust immune activation in the mother at 2 and 4 hrs after LPS administration, while only IL-10 tended towards upregulation at 2 hrs after LPS in fetal brains. To evaluate the functional long-term consequences, we assessed learning and cognitive flexibility behavior during late adolescence, finding that LPS affects only the latter with a male predominance on perseveration. A CX3CR1 gene variant in humans that results in disrupted fractalkine signaling has been recently associated with an increased risk for neurodevelopmental disorders. We show that an acute immune insult during late gestation can alter fractalkine signaling by reducing the microglial CX3CR1 protein expression, highlighting neuron-microglial fractalkine signaling as a relevant target underlying the outcomes of environmental risk factors on neurodevelopmental disorders.     

Effects of early or late prenatal immune activation in mice on behavioral and neuroanatomical abnormalities relevant to schizophrenia in the adulthood

Maternal immune activation (MIA) during pregnancy in rodents increases the risk of the offspring to develop schizophrenia-related behaviors, suggesting a relationship between the immune system and the brain development. Here we tested the hypothesis that MIA induced by the viral mimetic polyinosinic-polycytidylic acid (poly I:C) in early or late gestation of mice leads to behavioral and neuroanatomical disorders in the adulthood. On gestational days (GDs) 9 or 17 pregnant dams were treated with poly I:C or saline via intravenous route and the offspring behaviors were measured during adulthood. Considering the progressive structural neuroanatomical alterations in the brain of individuals with schizophrenia, we used magnetic resonance imaging (MRI) to perform brain morphometric analysis of the offspring aged one year. MIA on GD9 or GD17 led to increased basal locomotor activity, enhanced motor responses to ketamine, a psychotomimetic drug, and reduced time spent in the center of the arena, suggesting an increased anxiety-like behavior. In addition, MIA on GD17 reduced glucose preference in the offspring. None of the treatments altered the relative volume of the lateral ventricles. However, a decrease in brain volume, especially for posterior structures, was observed for one-year-old animals treated with poly I:C compared with control groups. Thus, activation of the maternal immune system at different GDs lead to neuroanatomical and behavioral alterations possibly related to the positive and negative symptoms of schizophrenia. These results provide insights on neuroimmunonological and neurodevelopmental aspects of certain psychopathologies, such as schizophrenia.     

Fc receptors and the common gamma-chain in experimental autoimmune encephalomyelitis

Fcgamma receptors (FcgammaRs), composed of a ligand-binding alpha-chain (FcRalpha) sometimes associated with the homodimeric, cell-signaling common gamma-chain (FcRgamma), comprise an important family of effector molecules linking humoral and cell-mediated adaptive immunity and regulating innate immunity. In peripheral autoimmune diseases, FcgammaRs contribute to inflammation and tissue damage through inappropriate activation of macrophages and neutrophils, release of cytokines and oxidants, and destruction of autoantibody-opsonized cells. In the central nervous system (CNS), the role of FcgammaRs in autoimmune disease such as multiple sclerosis (MS) remains largely unexplored despite extensive documentation of CNS-specific antibodies in cerebrospinal fluid and plaques. Several studies have now examined the role of FcgammaRs in experimental autoimmune encephalomyelitis (EAE), the animal model for MS, using mice genetically deficient in one or more FcgammaRs or in FcRgamma. These studies indicate that none of the FcgammaR alpha-chains are critical for EAE development and progression. In contrast, it is unequivocal that FcRgamma contributes to EAE, and surprisingly it seems that this effect is independent of FcgammaRs. Recent studies now indicate that FcRgamma expression in gammadelta T cells, most likely as a component of the TCR/CD3 signaling complex, is a critical requirement for EAE development. These studies support previous evidence implicating a pathogenic role for gammadelta T cells in EAE.     

Effect of maternal immune activation on the kynurenine pathway in preadolescent rat offspring and on MK801-induced hyperlocomotion in adulthood: Amelioration by COX-2 inhibition

Infections during pregnancy and subsequent maternal immune activation (MIA) increase risk for schizophrenia in offspring. The progeny of rodents injected with the viral infection mimic polyI:C during gestation display brain and behavioural abnormalities but the underlying mechanisms are unknown. Since the blood kynurenine pathway (KP) of tryptophan degradation impacts brain function and is strongly regulated by the immune system, we tested if KP changes occur in polyI:C offspring at preadolescence. We also tested whether MK801-induced hyperlocomotion, a behaviour characteristic of adult polyI:C offspring, is prevented by adolescent treatment with celecoxib, a COX-2 inhibitor that impacts the KP. Pregnant rats were treated with polyI:C (4 mg/kg, i.v.) or vehicle on gestational day 19. Serum levels of KP metabolites were measured in offspring of polyI:C or vehicle treated dams at postnatal day (PND) 31–33 using HPLC/GCMS. Additional polyI:C or vehicle exposed offspring were given celecoxib or vehicle between PND 35 and 46 and tested with MK801 (0.3 mg/kg) in adulthood (PND > 90). Prenatal polyI:C resulted in increases in the serum KP neurotoxic metabolite quinolinic acid at PND 31–33 (105%, p = 0.014). In contrast, the neuroprotective kynurenic acid and its precursor kynurenine were significantly decreased (28% p = 0.027, and 31% p = 0.033, respectively). Picolinic acid, another neuroprotective KP metabolite, was increased (31%, p = 0.014). Adolescent treatment with celecoxib (2.5 and 5 mg/kg/day, i.p.) prevented the development of MK801-induced hyperlocomotion in adult polyI:C offspring. Our study reveals the blood KP as a potential mechanism by which MIA interferes with postnatal brain maturation and associated behavioural disturbances and emphasises the preventative potential of inflammation targeting drugs.     

Acute experimental autoimmune encephalomyelitis. Differences between T cell subsets in the blood and meningeal infiltrates in susceptible and resistant strains of guinea pigs

The percentages of early (active, high affinity-rosetting), late (total) T cells and TG cells (suppressor T cells) were determined longitudinally in the blood and meningeal infiltrating cells of Strain 13 (susceptibility) and Strain 2 (resistant) animals inoculated for acute EAE and in guinea pigs of both strains in which the disease was suppressed with myelin basic protein (MBP) in incomplete Freund's adjuvant (IFA). Reactivity of T cells to MBP and oligodendrocyte protein was tested using the antigen-reactive T cell test. After inoculation for acute EAE, a transient increase in circulating early T cells was found during the latent period in Strain 13 guinea pigs only, while both strains showed a decrease in early T cells later on. Low values of circulating TG cells were more apparent in Strain 13 than Strain 2. In infiltrating cells of the meninges, early T cell values were significantly higher in the meninges than in the blood (P less than 0.01) in Strain 13, but were only slightly elevated in Strain 2 animals. TG cell levels in meningeal infiltrates were slightly higher than corresponding blood levels in both strains. In animals which were given a suppressive regimen of MBP/IFA, circulating early T cells rose initially and showed normal values later on in both strains of guinea pigs. TG cell levels were slightly more increased in strain 13 than strain 2. In comparison to blood values, early T cells were higher in the CNS in Strain 13, and lower in the CNS in Strain 2. TG cell levels were increased over blood values in both strains. These quantitative discrepancies in T cell subset between Strain 13 and Strain 2 guinea pigs which had been inoculated for EAE might reflect a difference in the cell-mediated immune response to white matter antigens which might be related to the variation in susceptibility to EAE.