Elevated viral transcription factor levels in cortical blood vessels in schizophrenia

Context and Rationale: Schizophrenia is a pervasive and devastating mental disorder, but the current available treatments do not alleviate the most debilitating feature of the disease: the cognitive deficits, specifically impairments in working memory. Through a translational approach, which involves tracing the disorder from its etiologic components to its clinical manifestations, novel and effective treatment strategies can be developed. Although the etiology of schizophrenia is extremely complex, a predominant risk factor is immune overactivation early in life, especially in-utero, that persists into adulthood. Additionally, the core pathologic source of the working memory impairments can be traced to dysfunctional GABA circuitry in the dorsolateral prefrontal cortex (DLPFC). In a previous study using a relatively small sample of schizophrenia subjects, mRNA levels of IFITM, a broad-spectrum viral restriction factor, has been shown to be markedly elevated in the DLPFC. This localized elevation, when considered with IFITM’s role as marker of immune activity, suggests that IFITM may be related to both the GABA circuitry deficiency and the residual immune dysfunction characteristic of schizophrenia.\ud \ud Study Objectives: To further evaluate IFITM’s status in the DLPFC in schizophrenia, the present study had four aims: (1) replicate the finding of higher levels of IFITM mRNA in the prefrontal cortex in a larger cohort of schizophrenia subjects; (2) evaluate whether the IFITM elevation in schizophrenia is attributable to factors that are associated with, but not central to, the disorder; (3) determine the cell types that overexpress IFITM mRNA in schizophrenia; and (4) investigate whether higher IFITM mRNA levels are correlated with abnormal GABA-related marker mRNAs in the same schizophrenia subjects.\ud \ud Methods: We used quantitative PCR (qPCR) and in situ hybridization (ISH) with film and grain counting analyses to quantify IFITM mRNA levels in postmortem samples of prefrontal cortex area 9 of 57 schizophrenia subjects and 57 comparison subjects. We then compared the findings to previously reported mRNA expressions of GABA-related markers in the same cohort of schizophrenia subjects. Transcript levels for IFITM mRNA were also assessed by qPCR in the prefrontal cortex of monkeys chronically exposed to antipsychotic medications.\ud \ud Results: In schizophrenia subjects, IFITM mRNA levels were markedly higher in both qPCR and ISH analyses. The finding could not be attributed to infection- or inflammation-related cause of death, psychotropic medication use at time of death, or nicotine use at time of death. IFITM mRNA levels were not altered in the prefrontal cortex of antipsychotic-exposed monkeys. ISH analyses revealed that IFITM mRNA levels were predominantly elevated in cortical blood vessels in schizophrenia. Furthermore, higher IFITM mRNA levels measured by qPCR are associated with deficits in prefrontal GABA markers in schizophrenia. \ud \ud Conclusions: The localization of IFITM to blood vessels in the prefrontal cortex suggests that the viral restriction factor is involved in immunoprotection provided by the blood-brain barrier, which has also been shown to be disrupted in schizophrenia. Considering that indicators of neuroinflammation are a pervasive finding in schizophrenia and that alterations in both GABA-related markers and IFITM have been associated with inflammatory processes, the correlation between IFITM mRNA overexpression in blood vessels and deficits in GABA-related markers may be explained by an common upstream insult, such as maternal immune activation mediated by inflammatory cytokine elevation or chronic neuroinflammation.\u