HERV-W upregulation expression in bipolar disorder and schizophrenia: unraveling potential links to systemic immune/inflammation status.

BACKGROUND: Bipolar disorder (BD) and schizophrenia (SZ) are the two main mental disorders with unknown etiology that significantly impact individuals' quality of life. The potential pro-inflammatory role in their pathogenesis is postulated and Human Endogenous Retrovirus W (HERV-W) is an emerging candidate to modulate this pathogenic finding. HERVs, ancient retroviruses in the human genome, may play roles in inflammation and disease pathogenesis. Despite HERVs' involvement in autoimmune diseases, their influence on mental disorders remains underexplored. Therefore, the aim of this study was to assess the level of HERV-W-env expression and the systemic inflammatory profile through the concentration of IL-2, IL-4, IL-6, IL-10, TNF-α and INF-γ cytokines in BD and SZ patients. RESULTS: All participants showed HERV-W-env expression, but its expression was higher in mental disorder patients (p < 0.01) than in control. When separated, SZ individuals exhibited higher HERV-W expression than the control group (p < 0.01). Higher serum levels of TNF-α and IL-10 were found in BD (p = 0.0001 and p = 0.001, respectively) and SZ (p = 0.01) and p = 0.01, respectively) than in the control group, while SZ showed decreased levels IFN-γ and IL-2 as compared to controls (p = 0.05) and BD patients (p = 0.05), respectively. Higher TNF-α/IL-4 and TNF-α/IL-10 ratios, and lower IFN-γ/IL-10 were observed in BD and SZ patients than controls. Significant negative correlation between HERV-W-env expression and IL-10 (r=-0.47 p < 0.05), as well as positive correlations between HERV-W-env expression and TNF-α/IL-10 or IFN-γ/IL-10 ratios (r = 0.48 p < 0.05 and r = 0.46 p < 0.05, respectively) were found in BD patients. CONCLUSION: These findings suggest not only a potential link between HERV-W-env expression both in BD and SZ, but also a possible involvement of systemic inflammatory status in BD patients.

HERV-W Envelope Triggers Abnormal Dopaminergic Neuron Process through DRD2/PP2A/AKT1/GSK3 for Schizophrenia Risk.

An increasing number of studies have begun considering human endogenous retroviruses (HERVs) as potential pathogenic phenomena. Our previous research suggests that HERV-W Envelope (HERV-W ENV), a HERV-W family envelope protein, is elevated in schizophrenia patients and contributes to the pathophysiology of schizophrenia. The dopamine (DA) hypothesis is the cornerstone in research and clinical practice related to schizophrenia. Here, we found that the concentration of DA and the expression of DA receptor D2 (DRD2) were significantly higher in schizophrenia patients than in healthy individuals. Intriguingly, there was a positive correlation between HERV-W ENV and DA concentration. Depth analyses showed that there was a marked consistency between HERV-W ENV and DRD2 in schizophrenia. Studies in vitro indicated that HERV-W ENV could increase the DA concentration by regulating DA metabolism and induce the expression of DRD2. Co-IP assays and laser confocal scanning microscopy indicated cellular colocalization and a direct interaction between DRD2 and HERV-W ENV. Additionally, HERV-W ENV caused structural and functional abnormalities of DA neurons. Further studies showed that HERV-W ENV could trigger the PP2A/AKT1/GSK3 pathway via DRD2. A whole-cell patch-clamp analysis suggested that HERV-W ENV enhanced sodium influx through DRD2. In conclusion, we uncovered a relationship between HERV-W ENV and the dopaminergic system in the DA neurons. Considering that GNbAC1, a selective monoclonal antibody to the MSRV-specific epitope, has been promised as a therapy for treating type 1 diabetes and multiple sclerosis (MS) in clinical trials, understanding the precise function of HERV-W ENV in the dopaminergic system may provide new insights into the treatment of schizophrenia.

COVID-19 Infection-Related Weight Loss Decreases Eating/Swallowing Function in Schizophrenic Patients.

BACKGROUND: In older people with psychoneurological diseases, COVID-19 infection may be associated with a risk of developing or exacerbating dysphagia. The aim of the present study was to examine the relationship between eating/swallowing function and COVID-19 infection. METHODS: Subjects were 44 inpatients with confirmed COVID-19 infection being treated for schizophrenia in a psychiatric ward. Eating function was assessed using the Food Intake Level Scale (FILS) before and after infection. We also evaluated age, comorbidities, COVID-19 hospital stay, obesity index, weight loss rate, and chlorpromazine equivalent. RESULTS: Subjects had a mean age of 68.86 years. Pre-infection, 20 subjects had a FILS score of 7-9 (presence of eating/swallowing disorder) and 24 subjects had a score of 10 (normal). Eating function after infection resolution showed decreasing FILS score compared to that before infection in 14 subjects (74.14 years). Six subjects (79.3 years) transitioned from oral feeding to parenteral feeding. A ≥ 10% weight loss during infection treatment was significantly associated with decreased eating function and a transition to parenteral feeding. Chlorpromazine equivalents, comorbidities, and number of days of hospitalization showed no associations with decreased eating function. CONCLUSIONS: Preventing malnutrition during treatment for COVID-19 infection is important for improving post-infection life prognosis and maintaining quality of life (QOL).

HERV-W env regulates calcium influx via activating TRPC3 channel together with depressing DISC1 in human neuroblastoma cells.

The activation and involvement of human endogenous retroviruses W family envelope gene (HERV-W env, also called ERVWE1) have been reported in several neuropsychiatric disorders, including schizophrenia, as well as in multiple sclerosis (MS). Dysregulation of intracellular calcium content is also involved in the pathogenesis of these diseases. Our previous studies showed that HERV-W env overexpression results in activation of small conductance Ca2+-activated K+ channel protein 3 (SK3), a potential risk factor for schizophrenia. In the present study, we aimed to elucidate the relationship between HERV-W env and calcium signaling in schizophrenia. Our results showed that HERV-W env could induce Ca2+ influx in two human neuroblastoma cell lines and upregulate the expression and activation of TRPC3 in cells. The abnormal increase in intracellular Ca2+ concentration was inhibited by addition of the TRPC3 channel blocker pyr3, demonstrating that the Ca2+ influx induced by HERV-W env was TRPC3-dependent. Further experiments showed that HERV-W env overexpression downregulated DISC1, while knockdown of DISC1 promoted activation of TRPC3 without affecting TRPC3 expression. In conclusion, HERV-W env induced Ca2+ influx in human neuroblastoma cells by activating the TRPC3 channel through directly regulating its expression or downregulating DISC1, which could also increase TRPC3 activation without affecting TRPC3 expression. These findings provide new insights into how HERV-W env affects neuronal activity and contributes to the pathogenesis of schizophrenia.

The association among smoking, HSV-1 exposure, and cognitive functioning in schizophrenia, bipolar disorder, and non-psychiatric controls.

Previous investigations have found that smokers with schizophrenia demonstrate reduced performance on cognitive tasks compared to non-smokers. However previous studies have not taken into account other environmental factors associated with cognitive functioning such as exposure to Herpes Simplex Virus type 1 (HSV-1). We examined these factors in a sample consisting of individuals with schizophrenia (n=773), bipolar disorder (n=493), or controls without a psychiatric disorders (n=548). Participants were assessed on a cognitive battery, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and had a blood sample drawn to measure seropositivity to HSV-1. Within each group linear regression models were constructed to determine whether cigarette smoking and HSV-1 seropositivity were jointly associated with cognitive functioning after adjusting for relevant covariates. Within the schizophrenia group, the effect size of lower total cognitive score was -0.279 (p<0.0001) for individuals who were both smokers and HSV-1 seropositive and a significant effect was found in all cognitive domains. The odds of being in the highest quartile of RBANS Total score were significantly lower for smokers (OR=0.58, 95% CI 0.41, 0.82, p=0.002). Smoking was not as consistently associated with levels of cognitive functioning in the bipolar disorder or the non-psychiatric control group. While experimental studies show that nicotine transiently improves functioning on sensory gating and attention tasks known to be deficient in schizophrenia, long-term nicotine exposure via smoking appears to have an adverse effect on cognitive functioning.

Expression and regulation of human endogenous retrovirus W elements.

Human endogenous retroviruses (HERV) comprise 8% of the human genome and can be classified into at least 31 families. A typical HERV provirus consists of internal gag, pol and env genes, flanked by two long terminal repeats (LTRs). No single provirus is capable of engendering infectious particles. HERV are by nature repetitive and have with few notable exceptions lost their protein-coding capacity. Therefore, HERV have consistently been excluded from array-based expression studies and hence little is known of their expression, regulation, and potential functional significance. An increasing number of studies have, however, observed expression of the W family of HERV in various human tissues and cells, predominantly in placenta. HERV-W LTRs act as promoters in directing transcription of HERV-W members, contribute to their tissue-specific and highly diversified expression pattern. Furthermore, leaky transcription originating from adjacent genes plays a role in the transcription initiation of HERV-W psudoelements. It has been reported that HERV-W elements, including ERVWE1 (the so far only known HERV-W locus harboring a gene (env) functionally adopted by the human host to critically participate in placenta biogenesis), can become transactivated in a range of human non-placental cell-lines during exogenous virus infections. Aberrant expression of HERV-W has been associated with human diseases, such as cancer, multiple sclerosis, and schizophrenia. Based on published reports, transcriptional activities of HERV-W appear to be influenced by several mechanisms; binding of transcription factors to LTR promoters and enhancers outside of LTRs, genetic variation and alteration in DNA methylation and histone modification. Emerging mechanistic studies support the notion that HERV-W represents a potential marker or mediator of environmental exposures (e.g., virus infection) in the development of chronic complex diseases.

Human endogenous retroviruses in neurologic disease.

Endogenous retroviruses are pathogenic - in other species than the human. Disease associations for Human Endogenous RetroViruses (HERVs) are emerging, but so far an unequivocal pathogenetic cause-effect relationship has not been established. A role for HERVs has been proposed in neurological and neuropsychiatric diseases as diverse as multiple sclerosis (MS) and schizophrenia (SCZ). Particularly for MS, many aspects of the activation and involvement of specific HERV families (HERV-H/F and HERV-W/MSRV) have been reported, both for cells in the circulation and in the central nervous system. Notably envelope genes and their gene products (Envs) appear strongly associated with the disease. For SCZ, for ALS, and for HIV-associated dementia (HAD), indications are accumulating for involvement of the HERV-K family, and also HERV-H/F and/or HERV-W. Activation is reasonably a prerequisite for causality as most HERV sequences remain quiescent in non-pathological conditions, so the importance of regulatory pathways and epigenetics involved in regulating HERV activation, derepression, and also involvement of retroviral restriction factors, is emerging. HERV-directed antiretrovirals have potential as novel therapeutic paradigms in neurologic disease, particularly in MS. The possible protective or ameliorative effects of antiretroviral therapy in MS are substantiated by reports that treatment of HIV infection may be associated with a significantly decreased risk of MS. Further studies of HERVs, their role in neurologic diseases, and their potential as therapeutic targets are essential.

Infection and inflammation in schizophrenia and bipolar disorder: a genome wide study for interactions with genetic variation.

Inflammation and maternal or fetal infections have been suggested as risk factors for schizophrenia (SZ) and bipolar disorder (BP). It is likely that such environmental effects are contingent on genetic background. Here, in a genome-wide approach, we test the hypothesis that such exposures increase the risk for SZ and BP and that the increase is dependent on genetic variants. We use genome-wide genotype data, plasma IgG antibody measurements against Toxoplasma gondii, Herpes simplex virus type 1, Cytomegalovirus, Human Herpes Virus 6 and the food antigen gliadin as well as measurements of C-reactive protein (CRP), a peripheral marker of inflammation. The subjects are SZ cases, BP cases, parents of cases and screened controls. We look for higher levels of our immunity/infection variables and interactions between them and common genetic variation genome-wide. We find many of the antibody measurements higher in both disorders. While individual tests do not withstand correction for multiple comparisons, the number of nominally significant tests and the comparisons showing the expected direction are in significant excess (permutation p=0.019 and 0.004 respectively). We also find CRP levels highly elevated in SZ, BP and the mothers of BP cases, in agreement with existing literature, but possibly confounded by our inability to correct for smoking or body mass index. In our genome-wide interaction analysis no signal reached genome-wide significance, yet many plausible candidate genes emerged. In a hypothesis driven test, we found multiple interactions among SZ-associated SNPs in the HLA region on chromosome 6 and replicated an interaction between CMV infection and genotypes near the CTNNA3 gene reported by a recent GWAS. Our results support that inflammatory processes and infection may modify the risk for psychosis and suggest that the genotype at SZ-associated HLA loci modifies the effect of these variables on the risk to develop SZ.

Metagenomic Sequencing Indicates That the Oropharyngeal Phageome of Individuals With Schizophrenia Differs From That of Controls.

Mucosal sites such as the oropharynx contain a wide range of microorganisms, collectively designated as the microbiome. The microbiome can affect behavior through a number of neurobiological and immunological mechanisms. Most previous studies have focused on the bacterial components of the microbiome. However, the microbiome also includes viruses such as bacteriophages, which are viruses that infect bacteria and alter their metabolism and replication. We employed metagenomic analysis to characterize bacteriophage genomes in the oral pharynx of 41 individuals with schizophrenia and 33 control individuals without a psychiatric disorder. This analysis was performed by the generation of more than 100,000,000 sequence reads from each sample and the mapping of these reads to databases. We identified 79 distinct bacteriophage sequences in the oropharyngeal samples. Of these, one bacteriophage genome, Lactobacillus phage phiadh, was found to be significantly different in individuals with schizophrenia (P < .00037, q < 0.03 adjusted for multiple comparisons). The differential levels of Lactobacillus phage phiadh remained significant when controlling for age, gender, race, socioeconomic status, or cigarette smoking (P < .006). Within the group of individuals with schizophrenia, the level of Lactobacillus phage phiadh correlated with the prevalence of immunological disorders as well as with the administration of valproate, which has been shown in animal models to alter the microbiome. The bacteriophage composition of the oropharynx in individuals with schizophrenia differs from that of controls. The biological consequences of this difference and the potential effects of altering bacteriophage levels through therapeutic interventions are worthy of further investigation.

High prevalence of Human Herpesvirus 8 in schizophrenic patients.

Many studies have reported an association between Herpes family viruses and an increased risk of schizophrenia, but the role of Human Herpesvirus 8 (HHV8) has never been investigated. This study aimed to assess HHV8 prevalence in schizophrenic patients as well as the possible association between HHV8 infection and schizophrenia clinical features. We consecutively enrolled 108 patients meeting fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria of schizophrenia and 108 age and sex matched controls. Data about a number of demographic characteristics and potential HHV8 risk factors of infection were collected. Standardized psychopathology measures, disease severity and functioning level were obtained using Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms (SANS), Scale for the Assessment of Positive Symptoms (SAPS), Clinical Global Impressions (CGI) and Global Assessment of functioning (GAF). The presence of anti-HHV8 antibodies was analyzed using an indirect immunofluorescence assay. A higher prevalence of HHV8 infection in schizophrenic patients than in controls was found. Marital status, having children, sexual behavior and risk factors of blood transmission were not associated with HHV8 prevalence. However, among schizophrenic patients, HHV8 prevalence was statically associated with positive symptoms. To our knowledge, this would be the first report of a possible role of HHV8 in the pathogenesis of schizophrenia. To prove this hypothesis, further investigation of HHV8 in schizophrenia with larger samples is needed.

Evidence for Borna disease virus infection in neuropsychiatric patients in three western China provinces.

Borna disease virus (BDV) is a non-cytolytic, neurotropic RNA virus that can infect a wide variety of vertebrate species from birds and primates to humans. Several studies have been carried out to investigate whether BDV is associated with neuropsychiatric diseases. However, this association is still inconclusive. Two panels of subjects consisting of 1,679 various neuropsychiatric patients and healthy people from three western China provinces were enrolled in this study. BDV p24 or p40 RNA in peripheral blood mononuclear cells (PBMCs) were detected in the first panel of 1,481 subjects using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and cerebrospinal fluid (CSF) samples from the BDV RNA-positive individuals were subjected to BDV p24 antibodies testing by enzyme-linked immunosorbent assay (ELISA). BDV p24 or p40 RNA in PBMCs and p24 antibodies in plasma were detected in the second panel of 198 subjects by RT-qPCR and Western blot. A higher prevalence for BDV RNA was demonstrated in patients with viral encephalitis (6.70%), Guillain-Barré syndrome (6.70%), schizophrenia (9.90%) and chronic fatigue syndrome (CFS) (12.70%) compared to healthy controls in the first panel. CSF p24 antibodies were demonstrated in three viral encephalitis patients, two schizophrenia patients and two major depressive disorder (MDD) patients. The prevalences of p24 antibodies in plasma from patients with viral encephalitis (13.24%), multiple sclerosis (25.00%) and Parkinson's disease (22.73%) were significantly higher than healthy controls. This study demonstrates that BDV infection also exists in humans from three western China provinces, and suggests the involvement of the contribution of BDV in the aetiology of Chinese patients with some neuropsychiatric disorders, including viral encephalitis, schizophrenia, CFS, multiple sclerosis and Parkinson's disease.

GABBR1 has a HERV-W LTR in its regulatory region--a possible implication for schizophrenia.

Schizophrenia is a complex disease with uncertain aetiology. We suggest GABBR1, GABA receptor B1 implicated in schizophrenia based on a HERV-W LTR in the regulatory region of GABBR1. Our hypothesis is supported by: (i) GABBR1 is in the 6p22 genomic region most often implicated in schizophrenia; (ii) microarray studies found that only presynaptic pathway-related genes, including GABA receptors, have altered expression in schizophrenic patients and (iii) it explains how HERV-W elements, expressed in schizophrenia, play a role in the disease: by altering the expression of GABBR1 via a long terminal repeat that is also a regulatory element to GABBR1.

Antibodies to retroviruses in recent onset psychosis and multi-episode schizophrenia.

BACKGROUND: Immunological abnormalities involving the upregulation of endogenous retroviruses have been associated with schizophrenia in small studies. METHODS: Blood samples from 666 individuals (163 with recent onset psychosis, 268 with multi-episode schizophrenia, and 235 controls) were assayed for IgG antibodies to murine leukemia virus (MuLV), Mason-Pfizer monkey virus (MPMV), and feline immunodeficiency virus (FIV) by enzyme immunoassay utilizing whole virus and viral components. Antibody levels in the psychiatric groups were compared to controls by multivariate linear regression. Odds ratios associated with increased antibody levels were calculated based on values ≥ 75th percentile of the controls. Samples were also tested for antibodies to viral proteins by Western blotting and for DNA from infectious retroviruses by real time PCR. Homology between the target virus and the prototype human genome was determined using sequence analysis methods. RESULTS: Compared with controls, individuals with recent onset of psychosis had increased levels of antibodies to MPMV and MuLV (both p<.001 adjusted for covariates), and increased antibody levels for defined portions of the MPMV and MuLV gag, pol and env proteins. The specificity of these antibodies was confirmed by Western blotting. Individuals with multi-episode schizophrenia did not show elevated antibody levels to any of the retroviruses measured. Infectious retroviruses were not detected in the blood of any participants. Homology analyses indicated that there are multiple regions of the human genome homologous with MPMV and MuLV proteins, the highest being with the MuLV gag protein. CONCLUSIONS: Antibodies to retroviral proteins are elevated in individuals with recent onset psychosis but not in individuals with multi-episode schizophrenia. The immunopathological consequences of this antibody response should be the subject of additional studies.

Absence of evidence for bornavirus infection in schizophrenia, bipolar disorder and major depressive disorder.

In 1983, reports of antibodies in subjects with major depressive disorder (MDD) to an as-yet uncharacterized infectious agent associated with meningoencephalitis in horses and sheep led to molecular cloning of the genome of a novel, negative-stranded neurotropic virus, Borna disease virus (BDV). This advance has enabled the development of new diagnostic assays, including in situ hybridization, PCR and serology based on recombinant proteins. Since these assays were first implemented in 1990, more than 80 studies have reported an association between BDV and a wide range of human illnesses that include MDD, bipolar disorder (BD), schizophrenia (SZ), anxiety disorder, chronic fatigue syndrome, multiple sclerosis, amyotrophic lateral sclerosis, dementia and glioblastoma multiforme. However, to date there has been no blinded case-control study of the epidemiology of BDV infection. Here, in a United States-based, multi-center, yoked case-control study with standardized methods for clinical assessment and blinded serological and molecular analysis, we report the absence of association of psychiatric illness with antibodies to BDV or with BDV nucleic acids in serially collected serum and white blood cell samples from 396 subjects, a study population comprised of 198 matched pairs of patients and healthy controls (52 SZ/control pairs, 66 BD/control pairs and 80 MDD/control pairs). Our results argue strongly against a role for BDV in the pathogenesis of these psychiatric disorders.

Implication of the env gene of the human endogenous retrovirus W family in the expression of BDNF and DRD3 and development of recent-onset schizophrenia.

OBJECTIVE: Retrovirus has been suggested as one of agents involved in the development of schizophrenia. In the present study, we examined the role of the human endogenous retrovirus W family (HERV-W) env gene in the etiopathogenesis of recent-onset schizophrenia, using molecular and epidemiological approaches. METHODS: Nested RT-PCR was used to detect the messenger RNA (mRNA) of the HERV-w env gene in plasmas. Quantitative real-time polymerase chain reaction (PCR) was employed to detect the viral reverse transcriptase activity in human sera. Human U251 glioma cells were used to study the potential role of the HERV-W env gene in the etiopathogenesis of recent-onset schizophrenia. RESULTS: We identified genes with mRNA sequences homologous to HERV-W env gene from plasmas of 42 out of 118 individuals with recent-onset schizophrenia but not from any of 106 normal persons (P < .01, t test). Quantitative real-time PCR showed a significantly increase in the reverse transcriptase activity in the sera of patients (by 35.59%) compared with controls (by 2.83%) (P < .05, t test). Overexpression of HERV-w env in human U251 glioma cells upregulated brain-derived neurotrophic factor (BDNF), an important schizophrenia-associated gene, neurotrophic tyrosine kinase receptor type 2 (NTRK2, also called TrkB), and dopamine receptor D3 and increased the phosphorylation of cyclic adenosine monophosphate response element-binding (CREB) protein. BDNF promoter reporter gene assays showed that the HERV-W env triggers BDNF production in human U251 glioma cells. Using gene knockdown, we found that CREB is required for the expression of BDNF that is regulated by env. CONCLUSION: Our data revealed that the transcriptional activation of HERV is associated with the development of schizophrenia in some patients and indicated that HERV-W env regulates the expression of schizophrenia-associated genes. This report is the first to elucidate the signaling pathway responsible for the upregulation of HERV-W env-triggered BDNF. Our study provides new evidence for the involvement of HERV-W in the central nervous system, which will benefit the diagnosis and treatment of the devastating schizophrenia and related disorders.

Effect of cytomegalovirus infection on temporal lobe development in utero: quantitative MRI studies.

Several environmental factors, including viral infections during fetal development, are known to increase the risk of schizophrenia. Cytomegalovirus (CMV) is the main cause of viral congenital infection. Since changes in temporal lobe structures are a consistent finding in imaging studies of adult schizophrenics, we investigated possible derangement in temporal lobe development in CMV infected fetuses. Abdominal MRI (1.5 T) was performed using a single-shot fast spin echo T2-weighted sequence. MRI volumetry was employed to measure brain and temporal lobe size in 27 CMV infected fetuses and 52 gestational age matched controls in utero. The ratio of temporal lobe to whole brain was computed for each fetus and group comparisons were performed using Student's t-test or ANOVA. Temporal lobe volumes, normalized to whole brain and co-varied with gestational age; were significantly smaller in fetuses infected with CMV compared to uninfected fetuses. (Infected group mean ± SEM: 0.086 ± 0.006, controls: 0.113 ± 0.003, p<0.0001). Infection during the 1st and 2nd trimester had a more pronounced effect than infection during the 3rd trimester. Infected fetuses with no MRI findings had significantly lower temporal lobe/whole brain ratios than controls (0.092 ± 0.008, p<0.01, N=11) and the lowest ratios were observed in fetuses with overt findings such as cysts or gray matter heterotopy (0.067 ± 0.015). These results demonstrate the ability of quantitative fetal brain MRI to detect previously unreported, specific deficits in brain development in CMV infected fetuses, which, in conjunction with other genetic and environmental factors, may contribute to the risk of developing schizophrenia later in life.

HERVs in neuropathogenesis.

In humans, exogenous retroviruses are known to cause immunodeficiency and neurological disease. While endogenous retroviruses are firmly established pathogens in other species, the human endogenous retroviruses (HERVs) may well be considered as emerging pathogens. HERVs also exhibit complex interactions with exogenous retroviruses and herpesviruses. Two neurological disorders in particular are associated with HERVs: multiple sclerosis (MS) and schizophrenia. HERV-H/F and HERV-W are specifically activated both in the circulation and the central nervous system (CNS) in a majority of MS patients, and particularly, the envelopes (env transcription and Env proteins) appear strongly associated with disease activity. Interferon beta (IFN-beta) therapy is well-established for MS. IFN-beta is also known to have anti-retroviral activities toward exogenous retroviruses (HIV and HTLV-I). New reports show that IFN-beta also mediate down-regulation of HERV-H/F and HERV-W in MS patients. HERV-W and HERV-K transcription (gag and pol) appears, to some extent, to be up-regulated in the circulation and the CNS of patients with schizophrenia. The expression of anti-HERV-W Gag reactive epitopes is reported to be down-regulated in the brain but up-regulated in the blood from schizophrenia patients. The pathogenic potential of HERVs certainly merits further studies.

Cognitive impairment following prenatal immune challenge in mice correlates with prefrontal cortical AKT1 deficiency.

Accumulating evidence indicates that genetically determined deficiency in the expression of the cytoplasmic serine-threonine protein kinase AKT1 may contribute to abnormal prefrontal cortical structure and function relevant to the cognitive disturbances in schizophrenia. However, it remains essentially unknown whether prefrontal AKT1 expression may also be influenced by environmental factors implicated in the aetiology of this mental illness. One of the relevant environmental risk factors of schizophrenia and related disorders is prenatal exposure to infection and/or immune activation. This study therefore explored whether prenatal immune challenge may lead to prefrontal AKT1 deficiency and associated changes in cognitive functions attributed to the prefrontal cortex. For these purposes, we used a well-established experimental mouse model of prenatal exposure to a viral-like acute phase response induced by the synthetic analogue of double-stranded RNA, polyriboinosinic-polyribocytidilic acid (PolyI:C). We found that adult offspring born to PolyI:C-treated mothers showed delay-dependent impairments in spatial working memory and recognition memory together with a marked reduction of AKT1-positive cells in the prefrontal cortex. These effects emerged in the absence of concomitant changes in prefrontal catechol-O-methyltransferase (COMT) density. Correlative analyses further demonstrated a significant positive correlation between the number of AKT1-positive cells in distinct prefrontal cortical subregions and cognitive performance under high storage load in the temporal domain. Our findings thus highlight that schizophrenia-related alterations in AKT1 signalling and associated cognitive dysfunctions may not only be precipitated by genetically determined factors, but may also be produced by (immune-associated) environmental insults implicated in the aetiology of this disabling brain disorder.

Grey matter changes associated with host genetic variation and exposure to Herpes Simplex Virus 1 (HSV1) in first episode schizophrenia.

BACKGROUND: We previously reported reduced prefrontal cortex (PFC) grey matter volume among first episode, antipsychotic-naïve schizophrenia subjects (SZ) exposed to HSV1 but not among healthy subjects (HS) (Prasad et al., 2007). Independently, rs1051788, an exonic polymorphism of the MHC Class I polypeptide-related sequence B (MICB) gene was associated with HSV1 seropositivity, as well as SZ risk. In this study, we examined whether PFC grey matter changes associated with HSV1 exposure varied against the background of MICB genotypes. METHODS: We examined Caucasian individuals from the sample we studied in our previous report (Prasad et al., 2007) (SZ, n=21 and HS, n=19). Whole brain voxelwise analysis of structural MRI scans was conducted using Statistical Parametric Mapping, ver 5 (SPM5). The impact of rs1051788 variation and HSV1 seropositivity on grey matter volumes was examined using regression models on the combined sample of cases and controls, and then within each diagnostic group. RESULTS: In the combined sample of cases and controls, we observed the main effects of HSV1 seropositivity and genotypes, and a significant joint effect of HSV1 seropositivity and genotype mainly in the PFC. The joint effect was more prominent among cases than among controls. DISCUSSION: Our observations suggest that rs1051788 and HSV1 seropositivity are associated individually and jointly with reduced PFC grey matter volume. The patterns of these associations differ by diagnostic status, and these factors explain only a "small" portion of the variance in the grey matter volume reductions.

Clinicopathological study of early progressive multifocal leukoencephalopathy incidentally found in a schizophrenia patient.

A 58-year-old Japanese man developed psychomotor excitement and hallucinatory paranoia at age 53, which gradually developed to residual schizophrenia. He was administered various common tranquilizers until death. Myelodysplastic syndrome was noted 10 months before death. A routine autopsy was performed. The brain weighed 1365 g, and macroscopic observation revealed no remarkable findings. However, microscopic examination disclosed cells with enlarged and basophilic nuclei, and unusual astrocytes in the demyelinated foci, especially at the corticomedullary junctions in the temporal and occipital lobes. On the other hand, the white matter was relatively intact. Immunohistochemical analysis using anti-JC virus protein, VP-1 antibody, demonstrated JC virus-infected cells in not only abnormal glial cells and neurons but also normal-looking cells, which are suggestive of progressive multifocal leukoencephalopathy (PML). Immunostaining for GFAP revealed severe gliosis and some scattered abnormal enlarged nuclear cells in the lesions. Some clusters of CD8-positive lymphocytes were seen, which kill infected cells. PML could be considered a short-term disease preceding death, as "incidental PML" in this case. This is a rare autopsy case of early PML occurring in a schizophrenia patient with PML.