From early adversities to immune activation in psychiatric disorders: the role of the sympathetic nervous system.

Increased peripheral levels of cytokines and central microglial activation have been reported in patients with psychiatric disorders. The degree of both innate and adaptive immune activation is also associated with worse clinical outcomes and poor treatment response in these patients. Understanding the possible causes and mechanisms leading to this immune activation is therefore an important and necessary step for the development of novel and more effective treatment strategies for these patients. In this work, we review the evidence of literature pointing to childhood trauma as one of the main causes behind the increased immune activation in patients with psychiatric disorders. We then discuss the potential mechanisms linking the experience of early life adversity (ELA) to innate immune activation. Specifically, we focus on the innervation of the bone marrow from sympathetic nervous system (SNS) as a new and emerging mechanism that has the potential to bridge the observed increases in both central and peripheral inflammatory markers in patients exposed to ELA. Experimental studies in laboratory rodents suggest that SNS activation following early life stress exposure causes a shift in the profile of innate immune cells, with an increase in proinflammatory monocytes. In turn, these cells traffic to the brain and influence neural circuitry, which manifests as increased anxiety and other relevant behavioural phenotypes. To date, however, very few studies have been conducted to explore this candidate mechanism in humans. Future research is also needed to clarify whether these pathways could be partially reversible to improve prevention and treatment strategies in the future.

Translational evaluation of translocator protein as a marker of neuroinflammation in schizophrenia.

Positron emission tomography (PET) imaging with radiotracers that target translocator protein 18 kDa (TSPO) has become a popular approach to assess putative neuroinflammatory processes and associated microglia activation in psychotic illnesses. It remains unclear, however, whether TSPO imaging can accurately capture low-grade inflammatory processes such as those present in schizophrenia and related disorders. Therefore, we evaluated the validity of TSPO as a disease-relevant marker of inflammation using a translational approach, which combined neurodevelopmental and neurodegenerative mouse models with PET imaging in patients with recent-onset schizophrenia and matched controls. Using an infection-mediated neurodevelopmental mouse model, we show that schizophrenia-relevant behavioral abnormalities and increased inflammatory cytokine expression are associated with reduced prefrontal TSPO levels. On the other hand, TSPO was markedly upregulated in a mouse model of acute neurodegeneration and reactive gliosis, which was induced by intrahippocampal injection of kainic acid. In both models, the changes in TSPO levels were not restricted to microglia but emerged in various cell types, including microglia, astrocytes and vascular endothelial cells. Human PET imaging using the second-generation TSPO radiotracer [11C]DPA-713 revealed a strong trend towards reduced TSPO binding in the middle frontal gyrus of patients with recent-onset schizophrenia, who were previously shown to display increased levels of inflammatory cytokines in peripheral and central tissues. Together, our findings challenge the common assumption that central low-grade inflammation in schizophrenia is mirrored by increased TSPO expression or ligand binding. Our study further underscores the need to interpret altered TSPO binding in schizophrenia with caution, especially when measures of TSPO are not complemented with other markers of inflammation. Unless more selective microglial markers are available for PET imaging, quantification of cytokines and other inflammatory biomarkers, along with their molecular signaling pathways, may be more accurate in attempts to characterize inflammatory profiles in schizophrenia and other mental disorders that lack robust reactive gliosis.

Chronic exposure to haloperidol and olanzapine leads to common and divergent shape changes in the rat hippocampus in the absence of grey-matter volume loss.

BACKGROUND: One of the most consistently reported brain abnormalities in schizophrenia (SCZ) is decreased volume and shape deformation of the hippocampus. However, the potential contribution of chronic antipsychotic medication exposure to these phenomena remains unclear. METHOD: We examined the effect of chronic exposure (8 weeks) to clinically relevant doses of either haloperidol (HAL) or olanzapine (OLZ) on adult rat hippocampal volume and shape using ex vivo structural MRI with the brain retained inside the cranium to prevent distortions due to dissection, followed by tensor-based morphometry (TBM) and elastic surface-based shape deformation analysis. The volume of the hippocampus was also measured post-mortem from brain tissue sections in each group. RESULTS: Chronic exposure to either HAL or OLZ had no effect on the volume of the hippocampus, even at exploratory thresholds, which was confirmed post-mortem. In contrast, shape deformation analysis revealed that chronic HAL and OLZ exposure lead to both common and divergent shape deformations (q = 0.05, FDR-corrected) in the rat hippocampus. In particular, in the dorsal hippocampus, HAL exposure led to inward shape deformation, whereas OLZ exposure led to outward shape deformation. Interestingly, outward shape deformations that were common to both drugs occurred in the ventral hippocampus. These effects remained significant after controlling for hippocampal volume suggesting true shape changes. CONCLUSIONS: Chronic exposure to either HAL or OLZ leads to both common and divergent effects on rat hippocampal shape in the absence of volume change. The implications of these findings for the clinic are discussed.

Haloperidol and olanzapine mediate metabolic abnormalities through different molecular pathways.

The pathogenesis of antipsychotic-induced disturbances of glucose homeostasis is still unclear. Increased visceral adiposity has been suggested to be a possible mediating mechanism. The aim of this study was to investigate, in an animal model, the differential effects of olanzapine and haloperidol on visceral fat deposition (using magnetic resonance imaging(MRI)) and on critical nodes of the insulin signaling pathway (liver-protein levels of IRS2 (insulin receptor substrate 2), GSK3α (glycogen synthase kinase-3α), GSK3ß, GSK3α-Ser21, GSK3ß-Ser9). To this end, we studied male Sprague-Dawley rats treated with vehicle (n=8), haloperidol (2 mg kg(-1) per day, n=8), or olanzapine (10 mg kg(-1)per day, n=8), using osmotic minipumps, for 8 weeks. The haloperidol group showed a higher percentage of visceral fat than both the olanzapine group and the vehicle group, whereas there was no difference between the olanzapine and the vehicle group. In terms of insulin signaling pathway, the olanzapine group showed significantly reduced IRS2 levels, reduced phosphorylation of GSK3α and increased phosphorylation of GSK3ß, whereas there was no difference between the haloperidol and the vehicle group. Our data suggest that different molecular pathways mediate the disturbances of glucose homeostasis induced by haloperidol and olanzapine with a direct effect of olanzapine on the insulin molecular pathway, possibly partly explaining the stronger propensity of olanzapine for adverse effects on glucose regulation when compared with haloperidol in clinical settings.

Neuroprotective effects of metabotropic glutamate receptor ligands in a 6-hydroxydopamine rodent model of Parkinson's disease.

Increasing evidence implicates glutamate-mediated excitotoxicity as a contributory factor in dopaminergic cell death in the substantia nigra pars compacta (SNc) in Parkinson's disease (PD). Previous studies have suggested that metabotropic glutamate receptor (mGluR) ligands are neuroprotective against excitotoxicity in vitro. In the present study, the neurotoxin 6-hydroxydopamine (6-OHDA) produced a significant loss (61.2 +/- 8.9%; P < 0.01) of tyrosine hydroxylase-immunopositive (TH+) cells in both the SNc and striatal dopamine (58.02 +/- 1.27%; P < 0.05) in control male Sprague-Dawley rats. Both losses were significantly attenuated by sub-chronic (7 day) treatment with the Group I mGluR antagonists, 2-methyl-6(phenylethynyl)-pyridine (MPEP) or (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385); the Group II mGluR agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC); or the Group III mGluR agonist, L(+)-2-amino-4-phosphonobutyric acid (L-AP4). These data demonstrate a neuroprotective action of mGluR ligands in vivo against 6-OHDA toxicity that has important implications for the treatment of PD.