Manfred Schedlowski

Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia

Epidemiological studies have indicated an association between maternal bacterial and viral infections during pregnancy and the higher incidence of schizophrenia in the resultant offspring post-puberty. One hypothesis asserts that the reported epidemiological link is mediated by prenatal activation of the foetal immune system in response to the elevation of maternal cytokine level due to infection. Here, we report that pregnant mouse dams receiving a single exposure to the cytokine-releasing agent, polyriboinosinic-polyribocytidilic acid (PolyI:C; at 2.5, 5.0, or 10.0 mg/kg) on gestation day 9 produced offspring that subsequently exhibited multiple schizophrenia-related behavioural deficits in adulthood, in comparison to offspring from vehicle injected or non-injected control dams. The efficacy of the PolyI:C challenge to induce cytokine responses in naïve non-pregnant adult female mice and in foetal brain tissue when injected to pregnant mice were further ascertained in separate subjects: (i) a dose-dependent elevation of interleukin-10 was detected in the adult female mice at 1 and 6h post-injection, (ii) 12 h following prenatal PolyI:C challenge, the foetal levels of interleukin-1beta were elevated. The spectrum of abnormalities included impairments in exploratory behaviour, prepulse inhibition, latent inhibition, the US-pre-exposure effect, spatial working memory; and enhancement in the locomotor response to systemic amphetamine (2.5 mg/kg, i.p.) as well as in discrimination reversal learning. The neuropsychological parallels between prenatal PolyI:C treatment in mice and psychosis in humans, demonstrated here, leads us to conclude that prenatal PolyI:C treatment represents one of the most powerful environmental-developmental models of schizophrenia to date. The uniqueness of this model lies in its epidemiological and immunological relevance. It is, sui generis, ideally suited for the investigation of the neuropsychoimmunological mechanisms implicated in the developmental aetiology and disease processes of schizophrenia.

Immunological stress at the maternal-foetal interface : a link between neurodevelopment and adult psychopathology

Maternal infection during pregnancy is associated with a higher incidence of mental disorders, including schizophrenia, in the offspring in later life. Our recent attempt to study this link between prenatal immunological challenge and subsequent psychopathology has led to the establishment of a mouse model demonstrating the emergence of multiple psychotic-like phenotypes following immunological challenge on gestation day (GD) 9. However, little is known about the impact of similar in utero challenge at different times of pregnancy. Here, we compare the efficacy of identical maternal immune stimulation induced by the exposure to polyriboinosinic-polyribocytidilic acid (Poly(I:C)) at a dose of 5mg/kg (i.v.) on distinct days of gestation (GD 6, 9, 13 or 17). The offspring derived were then compared to those collected from vehicle- and non-treated dams in two paradigms of selective associative learning: latent inhibition (LI) and the US-pre-exposure effect (USPEE). LI deficiency was observed in animals born to dams treated with Poly(I:C) on GD 6, 9 or 13, but not in those on GD17. In contrast, a loss of the USPEE was equivalently seen in all Poly(I:C) treatment groups, regardless of treatment times. Evaluation of the acute cytokine response in a separate cohort of pregnant dams receiving Poly(I:C) challenge on either GD9 or GD17 revealed that the ratio of interleukin-10/tumor necrosis factor-alpha was elevated in the GD17 relative to the GD9 group. The present report thus provides evidence that the acute cytokine reaction as well as the long-term pattern of behavioural sequelae of maternal immune challenge can be affected by its precise timing during pregnancy. The present study provides further support to the use of the prenatal Poly(I:C) model in the elucidation of mechanisms involved in the aetiology and disease process of immuno-precipitated neurodevelopmental mental diseases, including but not limited to, schizophrenia.

Adult behavioral and pharmacological dysfunctions following disruption of the fetal brain balance between pro-inflammatory and IL-10-mediated anti-inflammatory signaling

Maternal infections during pregnancy increase the risk for schizophrenia and related disorders of putative neurodevelopmental origin in the offspring. This association has been attributed to enhanced expression of pro-inflammatory cytokines in the fetal environment in response to maternal immunological stimulation. In contrast, the specific roles of anti-inflammatory cytokines are virtually unknown in this context. Here, we demonstrate that genetically enforced expression of the anti-inflammatory cytokine interleukin (IL)-10 by macrophages attenuates the long-term behavioral and pharmacological consequences of prenatal immune activation in a mouse model of prenatal viral-like infection by polyriboinosinic–polyribocytidilic acid (PolyI:C; 2 mg/kg, intravenously). In the absence of a discrete prenatal inflammatory stimulus, however, enhanced levels of IL-10 at the maternal–fetal interface by itself also precipitates specific behavioral abnormalities in the grown offspring. This highlights that in addition to the disruptive effects of excess pro-inflammatory molecules, a shift toward enhanced anti-inflammatory signaling in prenatal life can similarly affect cognitive and behavioral development. Hence, shifts of the balance between pro- and anti-inflammatory cytokine classes may be a critical determinant of the final impact on neurodevelopment following early life infection or innate immune imbalances.

G protein-coupled receptor kinase 2 in multiple sclerosis and experimental autoimmune encephalomyelitis

Many modulators of inflammation, including chemokines, neuropeptides, and neurotransmitters signal via G protein-coupled receptors (GPCR). GPCR kinases (GRK) can phosphorylate agonist-activated GPCR thereby promoting receptor desensitization. Here we describe that in leukocytes from patients with active relapsing-remitting multiple sclerosis (MS) or with secondary progressive MS, GRK2 levels are significantly reduced. Unexpectedly, cells from patients during remission express even lower levels of GRK2. The level of GRK2 in leukocytes of patients after stroke, a neurological disorder with paralysis but without an autoimmune component, was similar to GRK2 levels in cells from healthy individuals. In addition, we demonstrate that the course of recombinant myelin oligodendrocyte glycoprotein (1–125)-induced experimental autoimmune encephalomyelitis (EAE), an animal model for MS, is markedly different in GRK2+/− mice that express 50% of the GRK2 protein in comparison with wild-type mice. Onset of EAE was significantly advanced by 5 days in GRK2+/− mice. The earlier onset of EAE was associated with increased early infiltration of the CNS by T cells and macrophages. Although disease scores in the first phase of EAE were similar in both groups, GRK2+/− animals did not develop relapses, whereas wild-type animals did. The absence of relapses in GRK2+/− mice was associated with a marked reduction in inflammatory infiltrates in the CNS. Recombinant myelin oligodendrocyte glycoprotein-induced T cell proliferation and cytokine production were normal in GRK2+/− animals. We conclude that down-regulation of GRK2 expression may have important consequences for the onset and progression of MS.

Brain Response to Visual Sexual Stimuli in Heterosexual and Homosexual Males

Although heterosexual and homosexual individuals clearly show differences in subjective response to heterosexual and homosexual sexual stimuli, the neurobiological processes underlying sexual orientation are largely unknown. We addressed the question whether the expected differences in subjective response to visual heterosexual and homosexual stimuli may be reflected in differences in brain activation pattern. Twenty‐four healthy male volunteers, 12 heterosexuals and 12 homosexuals, were included in the study. BOLD signal was measured while subjects were viewing erotic videos of heterosexual and homosexual content. SPM02 was used for data analysis. Individual sexual arousal was assessed by subjective rating. As compared to viewing sexually neutral videos, viewing erotic videos led to a brain activation pattern characteristic for sexual arousal in both groups only when subjects were viewing videos of their respective sexual orientation. Particularly, activation in the hypothalamus, a key brain area in sexual function, was correlated with sexual arousal. Conversely, when viewing videos opposite to their sexual orientation both groups showed absent hypothalamic activation. Moreover, the activation pattern found in both groups suggests that stimuli of opposite sexual orientation triggered intense autonomic response and may be perceived, at least to some extent, as aversive. Hum Brain Mapp, 2008.

Cortisol and Heart Rate Measures during Casino Gambling in Relation to Impulsivity

Problematic gambling behavior is thought to be influenced by neurobiological as well as environmental factors. In this study, we investigated the relationship among impulsivity, gambling behavior, the cardiovascular system and the hypothalamic-pituitary-adrenal axis activity in blackjack gamblers. Twenty-nine males were continuously monitored before, during and after a 90-min blackjack session in a casino wagering their own money and during a control condition where subjects played cards for accumulation of points. Heart rate and cortisol levels significantly increased with the onset of gambling and remained elevated throughout the test session compared to the control condition. After median split of impulsivity scores, high impulsivity subjects revealed significantly higher heart rate levels compared to the low impulsivity subgroup. Correlation analyses revealed a positive relationship between impulsivity scores and severity of pathological gambling. Impulsivity may be one important factor mediating gambling behavior and its accompanying autonomic response.

Acute amygdaloid response to systemic inflammation

The amygdala, a group of nuclei located in the medial temporal lobe, is a key limbic structure involved in mood regulation, associative learning, and modulation of cognitive functions. Functional neuroanatomical studies suggest that this brain region plays also an important role in the central integration of afferent signals from the peripheral immune system. In the present study, intracerebral electroencephalography and microdialysis were employed to investigate the electrophysiological and neurochemical consequences of systemic immune activation in the amygdala of freely moving rats. Intraperitoneal administration of bacterial lipopolysaccharide (100 μg/kg) induced with a latency of about 2 h a significant increase in amygdaloid neuronal activity and a substantial rise in extracellular noradrenaline levels. Activated neurons in the amygdaloid complex, identified by c-Fos immunohistochemistry, were mainly located in the central nucleus and, to a lesser extent, in the basolateral nucleus of the amygdala. Gene expression analysis in micropunches of the amygdala revealed that endotoxin administration induced a strong time-dependent increase in IL-1β, IL-6, and TNF-α mRNA levels indicating that these cytokines are de novo synthesized in the amygdala in response to peripheral immune activation. The changes in amygdaloid activity were timely related to an increase in anxiety-like behavior and decreased locomotor activity and exploration in the open-field. Taken together, these data give novel insights into different features of the acute amygdaloid response during experimental inflammation and provides further evidence that the amygdala integrates immune-derived information to coordinate behavioral and autonomic responses.

Effects of a comprehensive lifestyle modification program on quality-of-life in patients with ulcerative colitis: A twelve-month follow-up

Objective. To analyze the effects of a comprehensive lifestyle modification program on health-related quality-of-life, psychological distress, and clinical parameters in patients with ulcerative colitis (UC) 3- and 12 months after completion of the program. Material and methods. Sixty patients with UC in clinical remission or with low disease activity were randomly assigned to an intervention group or a usual-care control group. Comprehensive lifestyle modification consisted of a structured 60-h training program over a period of 10 weeks which included stress management training, psychoeducational elements, and self-care strategies. Quality-of-life, psychological distress, and clinical disease activity were assessed with standardized questionnaires (Inflammatory Bowel Disease Questionnaire (IBDQ); the MOS Short-Form 36 (SF-36); the Brief Symptom Inventory (BSI), and the Colitis Activity Index (CAI)) at baseline, and 3 months and 12 months after comprehensive lifestyle modification. Results. Three months after comprehensive lifestyle modification, patients in the intervention group showed significantly greater improvement in the SF-36 scale physical function (p=0.0175), and a significantly greater reduction in anxiety scores, measured with the BSI (p=0.0294). Use of relaxation techniques was a significant predictor of improvement in the psychological sum score after 3 months of therapy (p=0.034). Though 80% of patients with an initial IBDQ score <170 in the intervention group showed an improvement of >16 points after 3 months, no significant effects of the intervention were found on the IBDQ scales, or on clinical disease parameters, including CAI scores, self-assessed disease activity, hospitalizations, or medical consultations. Conclusions. These results are consistent with possible short-term benefits of a comprehensive lifestyle modification program on some aspects of quality-of-life and emotional well-being, but no effects were discernable 12 months after completion of therapy. Comprehensive lifestyle modification had no effect on clinical disease variables. The generalizability of these data is limited because of the inclusion of patients with a relatively low disease activity who were interested in integrative medicine.

Acute interferon β-1b administration alters hypothalamic-pituitary-adrenal axis activity, plasma cytokines and leukocyte distribution in healthy subjects

It has been suggested that the immune-endocrine communication plays an important role in development and progression of multiple sclerosis (MS). Interferon beta (IFN beta-1b) treatment is the therapy of choice in patients suffering from relapsing remitting or secondary chronic progressive multiple sclerosis. While typical adverse events of IFN beta-1b treatment such as flu-like symptoms or fatigue are well studied, little is known about the acute changes in the immune and neuroendocrine system. Therefore, we analyzed the short-term effects of IFN beta-1b on cortisol, epinephrine, norepinephrine, prolactin and growth hormone (GH) plasma levels before and 4, 8 and 24 h after IFN beta-1b administration in healthy subjects. Moreover, we determined heart rate, blood pressure, body temperature, leukocyte and lymphocyte subsets and plasma levels of interleukin (IL)-1 beta, IL-6, IL-10 and tumor necrosis factor (TNF)-alpha. IFN beta-1b led to an increase in body temperature and heart rate, and in parallel, elevated cortisol, prolactin and GH plasma levels at 4 and 8 h after IFN beta-1b injection. There were no significant alterations in blood pressure, norepinephrine or epinephrine plasma levels. Simultaneously, IFN beta-1b injection led to an immediate granulocytosis while concomitantly decreasing peripheral lymphocytes, especially natural killer (NK) cells. At the same time, IL-6, IL-10 and TNF-alpha plasma levels showed an overall increase. Overall, cytokine administration exerts strong stimulatory effects on the hypothalamic-pituitary-adrenal (HPA)-axis that may contribute to the side effects of IFN beta-1b therapy and affect the efficacy of IFN beta-1b treatment.

G protein-coupled receptor kinase 6 controls chronicity and severity of dextran sodium sulphate-induced colitis in mice

Background: Infiltration of inflammatory cells into the colon plays an important role in the onset and course of inflammatory bowel disease. G-protein-coupled receptor kinase 6 (GRK6) is an intracellular kinase that regulates the sensitivity of certain G-protein-coupled receptors, including those involved in the migration of inflammatory cells. Therefore, it is hypothesised that GRK6 plays a role in determining the course of inflammation. Aim: To analyse the role of GRK6 in the course of dextran sodium sulphate (DSS)-induced colitis. Methods: Colitis was induced by administering 1% DSS in drinking water to GRK6−/−, GRK6+/− and wild-type (WT) mice for 6 days. The severity of colitis was assessed on the basis of clinical signs, colon length and histology. Moreover, keratinocyte-derived chemokine (KC) levels, granulocyte infiltration, interleukin 1β (IL1β), CD4, CD8 and forkhead box protein P3 (FoxP3) expression in the colon were determined. In addition, regulatory T cell function in WT and GRK6−/− mice was analysed. The chemotactic response of granulocytes to colon culture supernatants was assessed using a transendothelial migration assay. Results: The severity of colitis was increased in GRK6−/− and GRK6+/− mice and was accompanied by increased KC levels and increased granulocyte infiltration. Moreover, the chemotactic response of GRK6−/− granulocytes to supernatants of colon cultures was enhanced. Interestingly, the WT mice completely recovered from colitis, whereas the GRK6−/− and GRK6+/− mice developed chronic colitis, which was accompanied by increased IL1β and CD4 expression and decreased FoxP3 expression. Moreover, regulatory T cell function was impaired in the GRK6−/− mice. Conclusions: The intracellular level of GRK6 is an important factor in determining the onset, severity and chronicity of DSS-induced colitis.