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Translational Psychiatry Mar 2017Although the precise pathogenesis of schizophrenia is unknown, genetic, biomarker and imaging studies suggest involvement of the immune system. In this study, we... (Meta-Analysis)
Meta-Analysis
Although the precise pathogenesis of schizophrenia is unknown, genetic, biomarker and imaging studies suggest involvement of the immune system. In this study, we performed a systematic review and meta-analysis of studies investigating factors related to the immune system in postmortem brains of schizophrenia patients and healthy controls. Forty-one studies were included, reporting on 783 patients and 762 controls. We divided these studies into those investigating histological alterations of cellular composition and those assessing molecular parameters; meta-analyses were performed on both categories. Our pooled estimate on cellular level showed a significant increase in the density of microglia (P=0.0028) in the brains of schizophrenia patients compared with controls, albeit with substantial heterogeneity between studies. Meta-regression on brain regions demonstrated this increase was most consistently observed in the temporal cortex. Densities of macroglia (astrocytes and oligodendrocytes) did not differ significantly between schizophrenia patients and healthy controls. The results of postmortem histology are paralleled on the molecular level, where we observed an overall increase in expression of proinflammatory genes on transcript and protein level (P=0.0052) in patients, while anti-inflammatory gene expression levels were not different between schizophrenia and controls. The results of this meta-analysis strengthen the hypothesis that components of the immune system are involved in the pathogenesis of schizophrenia.
Topics: Astrocytes; Autopsy; Brain; Case-Control Studies; Cell Count; Humans; Inflammation; Microglia; Oligodendroglia; Schizophrenia; Temporal Lobe; Transcriptome
PubMed: 28350400
DOI: 10.1038/tp.2017.4 -
Molecular Psychiatry Aug 2016Schizophrenia is a psychiatric disorder which has a lifetime prevalence of ~1%. Multiple candidate mechanisms have been proposed in the pathogenesis of schizophrenia.... (Review)
Review
Schizophrenia is a psychiatric disorder which has a lifetime prevalence of ~1%. Multiple candidate mechanisms have been proposed in the pathogenesis of schizophrenia. One such mechanism is the involvement of neuroinflammation. Clinical studies, including neuroimaging, peripheral biomarkers and randomized control trials, have suggested the presence of neuroinflammation in schizophrenia. Many studies have also measured markers of neuroinflammation in postmortem brain samples from schizophrenia patients. The objective of this study was to conduct a systematic search of the literature on neuroinflammation in postmortem brains of schizophrenia patients indexed in MEDLINE, Embase and PsycINFO. Databases were searched up until 20th March 2016 for articles published on postmortem brains in schizophrenia evaluating microglia, astrocytes, glia, cytokines, the arachidonic cascade, substance P and other markers of neuroinflammation. Two independent reviewers extracted the data. Out of 5385 articles yielded by the search, 119 articles were identified that measured neuroinflammatory markers in schizophrenic postmortem brains. Glial fibrillary acidic protein expression was elevated, lower or unchanged in 6, 6 and 21 studies, respectively, and similar results were obtained for glial cell densities. On the other hand, microglial markers were increased, lower or unchanged in schizophrenia in 11, 3 and 8 studies, respectively. Results were variable across all other markers, but SERPINA3 and IFITM were consistently increased in 4 and 5 studies, respectively. Despite the variability, some studies evaluating neuroinflammation in postmortem brains in schizophrenia suggest an increase in microglial activity and other markers such as SERPINA3 and IFITM. Variability across studies is partially explained by multiple factors including brain region evaluated, source of the brain, diagnosis, age at time of death, age of onset and the presence of suicide victims in the cohort.
Topics: Astrocytes; Autopsy; Brain; Cytokines; Female; Glial Fibrillary Acidic Protein; Humans; Inflammation; Male; Microglia; Neuroglia; Neuroimmunomodulation; Schizophrenia
PubMed: 27271499
DOI: 10.1038/mp.2016.90 -
Psychopharmacology May 2016Psychosocial stressors are a well-documented risk factor for mental illness. Neuroinflammation, in particular elevated microglial activity, has been proposed to mediate... (Review)
Review
RATIONALE
Psychosocial stressors are a well-documented risk factor for mental illness. Neuroinflammation, in particular elevated microglial activity, has been proposed to mediate this association. A number of preclinical studies have investigated the effect of stress on microglial activity. However, these have not been systematically reviewed before.
OBJECTIVES
This study aims to systematically review the effects of stress on microglia, as indexed by the histological microglial marker ionised calcium binding adaptor molecule 1 (Iba-1), and consider the implications of these for the role of stress in the development of mental disorders.
METHODS
A systematic review was undertaken using pre-defined search criteria on PubMed and EMBASE. Inclusion and data extraction was agreed by two independent researchers after review of abstracts and full text.
RESULTS
Eighteen studies met the inclusion criteria. These used seven different psychosocial stressors, including chronic restraint, social isolation and repeated social defeat in gerbils, mice and/or rats. The hippocampus (11/18 studies) and prefrontal cortex (13/18 studies) were the most frequently studied areas. Within the hippocampus, increased Iba-1 levels of between 20 and 200 % were reported by all 11 studies; however, one study found this to be a duration-dependent effect. Of those examining the prefrontal cortex, ∼75 % found psychosocial stress resulted in elevated Iba-1 activity. Elevations were also consistently seen in the nucleus accumbens, and under some stress conditions in the amygdala and paraventricular nucleus.
CONCLUSIONS
There is consistent evidence that a range of psychosocial stressors lead to elevated microglial activity in the hippocampus and good evidence that this is also the case in other brain regions. These effects were seen with early-life/prenatal stress, as well as stressors in adulthood. We consider these findings in terms of the two-hit hypothesis, which proposes that early-life stress primes microglia, leading to a potentiated response to subsequent stress. The implications for understanding the pathoaetiology of mental disorders and the development of new treatments are also considered.
Topics: Animals; Humans; Inflammation; Mental Disorders; Microglia; Psychoneuroimmunology; Psychotic Disorders; Stress, Psychological
PubMed: 26847047
DOI: 10.1007/s00213-016-4218-9 -
Journal of Neuroinflammation Jun 2015Animal studies show that peripheral inflammatory stimuli may activate microglial cells in the brain implicating an important role for microglia in sepsis-associated... (Review)
Review
BACKGROUND
Animal studies show that peripheral inflammatory stimuli may activate microglial cells in the brain implicating an important role for microglia in sepsis-associated delirium. We systematically reviewed animal experiments related to the effects of systemic inflammation on the microglial and inflammatory response in the brain.
METHODS
We searched PubMed between January 1, 1950 and December 1, 2013 and Embase between January 1, 1988 and December 1, 2013 for animal studies on the influence of peripheral inflammatory stimuli on microglia and the brain. Identified studies were systematically scored on methodological quality. Two investigators extracted independently data on animal species, gender, age, and genetic background; number of animals; infectious stimulus; microglial cells; and other inflammatory parameters in the brain, including methods, time points after inoculation, and brain regions.
RESULTS
Fifty-one studies were identified of which the majority was performed in mice (n = 30) or in rats (n = 19). Lipopolysaccharide (LPS) (dose ranging between 0.33 and 200 mg/kg) was used as a peripheral infectious stimulus in 39 studies (76 %), and live or heat-killed pathogens were used in 12 studies (24 %). Information about animal characteristics such as species, strain, sex, age, and weight were defined in 41 studies (80 %), and complete methods of the disease model were described in 35 studies (68 %). Studies were also heterogeneous with respect to methods used to assess microglial activation; markers used mostly were the ionized calcium binding adaptor molecule-1 (Iba-1), cluster of differentiation 68 (CD68), and CD11b. After LPS challenge microglial activation was seen 6 h after challenge and remained present for at least 3 days. Live Escherichia coli resulted in microglial activation after 2 days, and heat-killed bacteria after 2 weeks. Concomitant with microglial response, inflammatory parameters in the brain were reviewed in 23 of 51 studies (45 %). Microglial activation was associated with an increase in Toll-like receptor (TLR-2 and TLR-4), tumor necrosis factor alpha (TNF-α), and interleukin 1 beta (IL-1β) messenger ribonucleic acid (mRNA) expression or protein levels.
INTERPRETATION
Animal experiments robustly showed that peripheral inflammatory stimuli cause microglial activation. We observed distinct differences in microglial activation between systemic stimulation with (supranatural doses) LPS and live or heat-killed bacteria.
Topics: Animals; Delirium; Disease Models, Animal; Escherichia coli; Female; Inflammation; Lipopolysaccharides; Male; Mice; Microglia; Rats; Sepsis
PubMed: 26048578
DOI: 10.1186/s12974-015-0332-6 -
Schizophrenia Research Jan 2015Neuroinflammation and white matter pathology have each been independently associated with schizophrenia, and experimental studies have revealed mechanisms by which the... (Review)
Review
BACKGROUND
Neuroinflammation and white matter pathology have each been independently associated with schizophrenia, and experimental studies have revealed mechanisms by which the two can interact in vitro, but whether these abnormalities simultaneously co-occur in people with schizophrenia remains unclear.
METHOD
We searched MEDLINE, EMBASE, PsycINFO and Web of Science from inception through 12 January 2014 for studies reporting human data on the relationship between microglial or astroglial activation, or cytokines and white matter pathology in schizophrenia.
RESULTS
Fifteen studies totaling 792 subjects (350 with schizophrenia, 346 controls, 49 with bipolar disorder, 37 with major depressive disorder and 10 with Alzheimer's disease) met all eligibility criteria. Five neuropathological and two neuroimaging studies collectively yielded consistent evidence of an association between schizophrenia and microglial activation, particularly in white rather than gray matter regions. Ultrastructural analysis revealed activated microglia near dystrophic and apoptotic oligodendroglia, demyelinating and dysmyelinating axons and swollen and vacuolated astroglia in subjects with schizophrenia but not controls. Two neuroimaging studies found an association between carrier status for a functional single nucleotide polymorphism in the interleukin-1β gene and abnormal white as well as gray matter volumes in schizophrenia but not controls. A neuropathological study found that orbitofrontal white matter neuronal density was increased in schizophrenia cases exhibiting high transcription levels of pro-inflammatory cytokines relative to those exhibiting low transcription levels and to controls. Schizophrenia was associated with decreased astroglial density specifically in subgenual cingulate white matter and anterior corpus callosum, but not other gray or white matter areas. Astrogliosis was consistently absent. Data on astroglial gene expression, mRNA expression and protein concentration were inconsistent.
CONCLUSION
Neuroinflammation is associated with white matter pathology in people with schizophrenia, and may contribute to structural and functional disconnectivity, even at the first episode of psychosis.
Topics: Cytokines; Databases, Bibliographic; Humans; Inflammation; Neuroglia; Schizophrenia; White Matter
PubMed: 24948485
DOI: 10.1016/j.schres.2014.04.041 -
Experimental Neurology Apr 2012In the spinal cord, neuron and glial cells actively interact and contribute to neurofunction. Surprisingly, both cell types have similar receptors, transporters and ion... (Review)
Review
In the spinal cord, neuron and glial cells actively interact and contribute to neurofunction. Surprisingly, both cell types have similar receptors, transporters and ion channels and also produce similar neurotransmitters and cytokines. The neuroanatomical and neurochemical similarities work synergistically to maintain physiological homeostasis in the normal spinal cord. However, in trauma or disease states, spinal glia become activated, dorsal horn neurons become hyperexcitable contributing to sensitized neuronal-glial circuits. The maladaptive spinal circuits directly affect synaptic excitability, including activation of intracellular downstream cascades that result in enhanced evoked and spontaneous activity in dorsal horn neurons with the result that abnormal pain syndromes develop. Recent literature reported that spinal cord injury produces glial activation in the dorsal horn; however, the majority of glial activation studies after SCI have focused on transient and/or acute time points, from a few hours to 1 month, and peri-lesion sites, a few millimeters rostral and caudal to the lesion site. In addition, thoracic spinal cord injury produces activation of astrocytes and microglia that contributes to dorsal horn neuronal hyperexcitability and central neuropathic pain in above-level, at-level and below-level segments remote from the lesion in the spinal cord. The cellular and molecular events of glial activation are not simple events, rather they are the consequence of a combination of several neurochemical and neurophysiological changes following SCI. The ionic imbalances, neuroinflammation and alterations of cell cycle proteins after SCI are predominant components for neuroanatomical and neurochemical changes that result in glial activation. More importantly, SCI induced release of glutamate, proinflammatory cytokines, ATP, reactive oxygen species (ROS) and neurotrophic factors trigger activation of postsynaptic neuron and glial cells via their own receptors and channels that, in turn, contribute to neuronal-neuronal and neuronal-glial interaction as well as microglia-astrocytic interactions. However, a systematic review of temporal and spatial glial activation following SCI has not been done. In this review, we describe time and regional dependence of glial activation and describe activation mechanisms in various SCI models in rats. These data are placed in the broader context of glial activation mechanisms and chronic pain states. Our work in the context of work by others in SCI models demonstrates that dysfunctional glia, a condition called "gliopathy", is a key contributor in the underlying cellular mechanisms contributing to neuropathic pain.
Topics: Animals; Gliosis; Neuralgia; Neuroglia; Rats; Spinal Cord; Spinal Cord Injuries
PubMed: 22036747
DOI: 10.1016/j.expneurol.2011.10.010