Bradley D. Pearce

The Proinflammatory Cytokine, Interleukin-1α, Reduces Glucocorticoid Receptor Translocation and Function1

Proinflammatory cytokines have been shown to influence the expression and function of the glucocorticoid receptor (GR). Specifically, several studies have found that cytokines induce a decrease in GR function, as evidenced by reduced sensitivity to glucocorticoid effects on functional end points. To investigate the potential mechanism(s) involved, we examined the impact of the proinflammatory cytokine, interleukin-1α (IL-1α), on 1) GR translocation from cytoplasm to nucleus using GR immunostaining, 2) cytosolic radioligand GR binding, and 3) GR-mediated gene transcription in L929 cells stably transfected with the mouse mammary tumor virus-cholamphenicol acetyltransferase reporter gene. L929 cells were treated with IL-1α (100 and 1000 U/ml) for 24 h in the presence or absence of dexamethasone (Dex; 10 nm to 1 μM). IL-1α inhibited Dex-induced GR translocation and alone induced GR up-regulation. Pretreatment with IL-1α followed by Dex treatment for 1.5 h led to about 20% inhibition of Dex-induced GR-mediated...

Effects of Cytokines on Glucocorticoid Receptor Expression And Function

Our data indicate that the proinflammatory cytokine, IL-1alpha inhibits GR translocation and hormone-induced GR-mediated gene transcription, and, in conjunction with previous in vivo and in vitro studies, can be interpreted to suggest that cytokines have the capacity to contribute to glucocorticoid resistance and thus the pathophysiology of depression. In addition, data from our mouse viral studies in glucocorticoid deficient animals demonstrate that endogenous glucocorticoids modulate a delicate balance between viral defense and cytokine toxicity. Finally, the antidepressant, DMI, has been found to enhance GR translocation and GR-mediated gene transcription and thus may provide a useful strategy for adjusting neuroendocrine setpoints in vivo. Taken together, these findings suggest that factors which modulate glucocorticoid action (e.g. cytokines and antidepressants) will be relevant contributors to disease expression including behavioral toxicity and sickness behavior.

The Relationship Between Toxoplasma Gondii Infection and Mood Disorders in the Third National Health and Nutrition Survey

BACKGROUND Toxoplasma gondii (T. gondii) is a neurotropic protozoan parasite that causes persistent infection in humans. A substantial literature suggests that schizophrenia is associated with increased seroprevalence of T. gondii, but a possible link of the parasite with mood disorders has not been as thoroughly investigated. METHODS We examined the association of Toxoplasma-specific immunoglobulin G results with mood disorder outcomes in 7440 respondents from the third National Health and Nutrition Survey, which is a nationally representative sample of the United States noninstitutionalized civilian population. Regression models were adjusted for numerous potential confounders, including tobacco smoking and C-reactive protein levels. RESULTS No statistically significant associations were found between T. gondii seroprevalence and a history of major depression (n = 574; adjusted odds ratio [OR]: .8; 95% confidence interval [CI]: .5-1.2), severe major depression (n = 515; adjusted OR: .8; 95% CI: .6-1.2), dysthymia (n = 548; adjusted OR: 1.1; 95% CI: .7-1.8), or dysthymia with comorbid major depression (n = 242, adjusted OR: 1.2; 95% CI: .6-2.4), all p values were > .05, including analysis stratified by gender. However, there was a significant relationship between T. gondii seroprevalence and bipolar disorder type I for respondents in which both manic and major depression symptoms were reported (n = 41; adjusted OR: 2.4; 95% CI: 1.2-4.8; p < .05). CONCLUSIONS In a population-based sample, T. gondii seroprevalence is not elevated in unipolar mood disorders but is higher in a subset of respondents with a history of bipolar disorder type 1.

The Phosphodiesterase Type 4 Inhibitor, Rolipram, Enhances Glucocorticoid Receptor Function

Previous studies have demonstrated that antidepressants can enhance glucocorticoid receptor (GR) translocation and function, possibly through activation of cAMP and downstream cAMP dependent protein kinases. Accordingly, we examined GR function in cells treated with rolipram, a phosphodiesterase (PDE) type 4 inhibitor that antagonizes cAMP breakdown. Compared with vehicle-treated cells, rolipram alone and in combination with dexamethasone significantly enhanced GR function as measured in both mouse L929 cells and rat C6 glioma cells stably transfected with reporter genes driven by upstream glucocorticoid response elements. Roliprams facilitation of GR function was reversible by the GR antagonist, RU486, and was associated with reduced cytosloic GR binding, indicating rolipram enhancement of GR nuclear translocation. Finally, rolipram potently augmented GR enhancement by the antidepressant, desipramine. These findings broaden the potential pathways by which PDE type 4 inhibitors can influence cellular function and indicate that these agents may have special utility in disorders associated with impaired GR-mediated feedback inhibition.

Effects of viral infection on corticosterone secretion and glucocorticoid receptor binding in immune tissues

During an immune challenge it has been suggested that responding cells secrete cytokines which then stimulate the release of glucocorticoids. Glucocorticoids, in turn, are believed to bind to their receptors in target immune tissues and provide feedback inhibition on evolving immune responses. The foundations for this hypothesis have been drawn primarily from studies on animal models of autoimmune and/or inflammatory processes, and the relevance of these glucocorticoid-immune interactions to viral infections has not been extensively examined. Accordingly, we infected mice with lymphocytic choriomeningitis virus (LCMV) and measured plasma corticosterone and cytosolic glucocorticoid receptor (GR) binding at multiple time points throughout the day and throughout infection (days 3, 5, 7 and 10 post infection). Despite a vigorous immune response to this virus, LCMV infection was associated with minimal and transient increases in corticosterone secretion. Interestingly, however, significant decreases in cytosolic GR were found in immune tissues. Receptor decreases were characterized by a significant decrease in GR binding during the diurnal rise in corticosterone in the spleen and thymus of infected but not uninfected animals on days 5-10 post infection. In addition, in the morning on these days, GR binding in the spleen of infected mice was decreased compared to uninfected control mice. Following an acute injection of corticosterone on day 7 post infection, LCMV-infected animals exhibited a significantly greater decrease in splenic GR binding than uninfected control mice, suggesting an increased sensitivity to corticosterone in infected animals. No changes were found in the affinity (Kd) of the GR during infection, nor was there evidence of an infection-associated decrease in plasma corticosteroid binding globulin. The appearance of significant GR changes in the spleen and thymus, in the absence of significant elevations in corticosterone or decreases in its binding protein, suggests that cytokines and/or other factors produced within the immune tissues during infection either directly influenced GR number and/or function or influenced the local availability of corticosterone. Taken together, the results indicate that interactions between the neuroendocrine and immune systems can be modified at the level of the GR in the context of an ongoing immune response such as during a viral infection.

Viral infection of developing GABAergic neurons in a model of hippocampal disinhibition.

Mechanisms by which perinatal viral infections can disrupt hippocampal development and cause selective neuronal death may have implications for temporal lobe epilepsy and schizophrenia. Despite abnormalities of inhibitory interneurons in these diseases, the causal relationships between such neurotransmitter changes and viral infections remain unclear. This relationship was examined in a model in which rats, infected with lymphocytic choriomeningitis virus (LCMV) as neonates, manifest a gradual loss of hippocampal dentate granule cells and neuronal hyperexcitability. The current data demonstrate that GABAergic interneurons are dual immunostained for LCMV antigens prior to the loss of dentate granule cells, supporting the hypothesis that LCMV may disrupt developing inhibitory circuits causing unbalanced excitatory neurotransmission and the eventual death of dentate granule cells due to excitotoxicity.

Models and Mechanisms

The purpose of this chapter is to disentangle the various theories (or more appropriately, sub-theories) that have been described in previous chapters concerning the viral hypothesis for schizophrenia. In addition, the contribution of various animal models toward understanding the mechanisms proposed in these theories will be elucidated. This section is necessarily speculatively and is based on the overarching believe that both genetic and environmental factors contribute to schizophrenia. For most of the theories described, a schematic timeline depicts how environmental, genetic, and neurodevelopmental events could act in parallel, or in concert, to lead to psychopathology.

Autism, lateralisation, and handedness: A review of the literature and meta-analysis

A number of recent investigators have hypothesised a link between autism, left-handedness, and brain laterality. Their findings have varied widely, in part because these studies have relied on different methodologies and definitions. We conducted a systematic review and meta-analysis to assess the literature, with the hypothesis that there would be an association between autism and laterality that would be moderated by handedness, sex, age, brain region studied, and level of autism. From a broad search resulting in 259 papers, 54 were identified for inclusion in the literature review. This list was narrowed further to include only studies reporting results in the inferior frontal gyrus for meta-analysis, resulting in four papers. The meta-analysis found a moderate but non-significant effect size of group on lateralisation, suggesting a decrease in strength of lateralisation in the autistic group, a trend supported by the literature review. A subgroup analysis of sex and a meta-regression of handedness showed that these moderating variables did not have a significant effect on this relationship. Although the results are not conclusive, there appears to be a trend towards a relationship between autism and lateralisation. However, more rigorous studies with better controls and clearer reporting of definitions and results are needed.

Modeling the role of infections in the etiology of mental illness

Abstract There are numerous psychiatric disorders of unknown etiology that have been tentatively linked with microbial pathogens, particularly viruses. These include autism, major depression, bipolar disorder, schizophrenia, and chronic fatigue syndrome. These disorders likely have multiple contributing etiologies, and viruses or bacteria may be tapping into pathophysiological pathways that are shared by other environmental triggers. Animal models have been important for elucidating such pathways. Experiments in animals have demonstrated that infections can influence neurotransmission, cause neurobehavioral abnormalities, and produce developmental changes in the brain that become manifested latently, i.e. after sexual maturity. Animal models are helping to clarify the role of cytokines in sickness behavior, which could be relevant to major depression and chronic fatigue syndrome. Cytokines may also hold a central position in the neurodevelopmental origin for schizophrenia since there is emerging evidence that elevations in cytokines are associated with non-infectious obstetric complications (e.g. hypoxia) that have likewise been implicated as antecedents of schizophrenia. Nevertheless, infectious disease models in psychiatry have not come fully to fruition, and to realize their potential, they must continually incorporate new data from in vitro and human studies.

Toxoplasma gondii exposure affects neural processing speed as measured by acoustic startle latency in schizophrenia and controls

The prevalence of Toxoplasma gondii (TOXO) infection in schizophrenia (SCZ) is elevated compared to controls (odds ratio=2.73). TOXO infection is associated with psychomotor slowing in rodents and non-psychiatric humans. Latency of the acoustic startle response, an index of neural processing speed, is the time it takes for a startling stimulus to elicit the reflexive response through a three-synapse subcortical circuit. We report a significant slowing of latency in TOXO seropositive SCZ vs. seronegative SCZ, and in TOXO seropositive controls vs. seronegative controls. Latency was likewise slower in SCZ subjects than in controls. These findings indicate a slowing of neural processing speed with chronic TOXO infection; the slowest startle latency was seen in the TOXO seropositive SCZ group.