Distribution of HLA-DR-positive microglia in schizophrenia reflects impaired cerebral lateralization

Abstract

Immunological alterations have been demonstrated in peripheral blood and cerebrospinal fluid of patients with schizophrenia, while previous postmortem studies have provided an inconsistent picture as to the role of microglia in the context of schizophrenia. Microglial activation is a sensitive indicator of changes in the CNS microenvironment, such as inflammatory and neurodegenerative processes. The aim of the present postmortem study was to examine HLA class II (HLA-DR) expression on microglia in brain regions which are particularly relevant for schizophrenia, with regard to hemispheric lateralization. Dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), hippocampus and mediodorsal thalamus (MD) were studied in 16 cases with schizophrenia and 16 control subjects. Immunostaining was found in all brain regions and was not restricted to macrophage-like ameboid cells, but also appeared in ramified cells. Region-specific HLA-DR-positive cell density was not significantly different between cases with schizophrenia and controls. However, ameboid microglial cells were lateralized towards the right hemisphere in healthy subjects but not in the schizophrenia group (P=0.01). Postmortem interval correlated with ramified cell numbers in ACC/DLPFC (P=0.01/0.04) and ameboid cell density in hippocampus (P=0.03). Age, gender, duration of disease, medication dosage, storage delay and whole brain volume had no effect. Single case analysis revealed highly elevated microglial cell numbers in ACC and MD of two schizophrenic patients who had committed suicide during acute psychosis. In conclusion, the present data suggest the absence of microgliosis but decreased cerebral lateralization of ameboid microglia in schizophrenia.

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

“…Postmortem evidence is growing: brain microglial activation has been suggested in postmortem and positron emission tomography studies using (R)-[11C]PK11195, a ligand that recognizes the translocator protein [44][45][46][47]. Other postmortem studies have found increased numbers and structural degenerative impairments of human leukocyte antigen-antigen D related+ microglia in schizophrenia [48][49][50]. There is also some evidence from schizophrenia animal models showing progressive microglial activation, increased inducible nitric oxide synthase expression, and oxidative/nitrosative stress markers in the offspring of rats exposed to the viral mimetic polyriboinosinicpolyribocytidylic acid during pregnancy, which are prevented by the administration of clozapine [51].…”

Gunn rats with glial activation in the hippocampus show prolonged immobility time in the forced swimming test and tail suspension test

“…In particular, several postmortem brain studies indicate that activated microglia are involved in both schizophrenia (Steiner et al., 2006) and major depression (Bayer, Busleia, Havasb, & Falkaia, 1999; Steiner et al., 2011). In accordance with, microglial activation may be a common finding in the pathogenesis of both the psychiatric diseases.…”

Microglial Gene Expression Alterations in the Brains of Patients with Psychiatric Disorders

“…There were no statistically significant changes in the numbers of HLA-DR-positive cells in the anterior cingulate cortex [30,[33][34][35], dorsolateral prefrontal cortex [28,33,34], hippocampus [31,33,34,36], mediodorsal thalamus [33,34] and dentate gyrus [34] from patients with schizophrenia. CD68-positive microglia were not altered in the mediodorsal thalamus [37] and dorsolateral prefrontal cortex [38] in patients with schizophrenia.…”

“…Recent postmortem studies reported that microgliosis, labeled by HLA-DR, was increased in two schizophrenic patients in the anterior cingulate cortex and mediodorsal nucleus of the thalamus; both of these patients, who had acute psychosis, committed suicide [34]. Additionally, microgliosis was observed in the dorsolateral prefrontal cortex and mediodorsal nucleus for suicide cases [33].…”

“…For example, a previous study indicated that the postmortem interval was significantly correlated with the ramified cell numbers in the anterior cingulate cortex and dorsolateral prefrontal cortices as well as with the ameboid cell density in the hippocampus [34]. Notably, the effect of postmortem interval on the gene expression profile in a postmortem brain is generally low if the interval is shorter than 48 hours.…”