Differential expression of viral and virus-associated RNA transcripts in the brains of individuals with schizophrenia and bipolar disorder

92

tissue (cerebellum and frontal lobe) in individuals with schizophrenia (n= 17), bipolar disorder (n= 12), severe depression without psychotic features (n= 12), and normal controls ( n 23 ). CSF QU1N was elevated in the schizophrenia and bipolar groups compared with depression and normal controls (ANOVA, p < 0.01 ) and correlated with recent exacerbation of illness (r-0.33, p - 0 . 0 0 9 ) and with ratings of global severity of illness (r = 0.25, p = 0.006) but not with age, substance abuse, postmortem interval, or global severity of illness. Cerebellum QUIN levels were elevated in the schizophrenia and bipolar groups compared with depression and normal controls (ANOVA, p=0.0009). CSF and cerebellar QUIN levels were highly correlated (r-0.76, p<0.0001 ). Frontal lobe QUIN levels were also elevated in schizophrenia and bipolar disorder (ANOVA, p<0.16) but tess marked than in the cerebellum. QUIN thus appears to be another marker suggesting the presence of an infective, inflammatory, and/or autoimmune component in some individuals with schizophrenia and bipolar disorder.

SCREENING

FOR VIRAL

SEQUENCES OBTAINED

IN CSF AND POSTMORTEM

INDIVIDUALS BIPOLAR

WITH

NUCLEIC BRAIN

ACID TISSUE

individuals and normal controls for the presence of RNA sequences of retroviral origin. Preliminary data indicate that RNA ampliflable with this system is not present in the ventricular fluids but may be present in the brain tissue of some individuals.

Rcterence Perron et al. (1997) PNAS, 94, 7583 7588.

DIFFERENTIAL AND

EXPRESSION

VIRUS-ASSOCIATED

TRANSCRIPTS

IN THE

INDIVIDUALS

WITH

AND

DISORDER

BIPOLAR

OF VIRAL

RNA BRAINS

OF

SCHIZOPHRENIA

F. Yee, N.L. J o h n s t o n , F. Leister, S. Li, C.A. Ross*, E.F. Torrey, R . H . Yolken a n d the Stanley Neuropathology Consortium

Stanley Neuroviroh~o, Laboratory, *Depts. o['Psychiatrv and Neuroscience, Johns Hopkins University School q/ Medicine, Baltimore, MD 21205, USA

FROM

SCHIZOPHRENIA

OR

DISEASE

H. K a r l s s o n , F. Leister, N . L J o h n s t o n , R . H . Yolken a n d the Stanley N e u r o p a t h o l o g y C o n s o r t i u m

The Stanley Neuroviroh~g:v Lahoralory, Johns Hopkins University School q/' Medic&e, 720 Ruthmd ave./Ross 1133. Baltimore, MD 21205, USA Several factors suggest a possible viral involvement in the pathogenesis of schizophrenia. The DNA-viruses of the herpes family has received much attention due to their neurotropism. The aim of the present study was to screen CSF's obtained postmortem from affected patients and unaffected controls for the presence of herpesviruses. DNA was extracted from 17 individuals with schizophrenia, 12 with bipolar disorder, 12 with other mental illnesses and 8 unaffected individuals. Nested polymerase chain reactions (PCRI were used to detect the following herpesviruses: herpes simplex virus (HSV)-I and -2, human herpesvirus (HHV)-6 and -8, cytomegalovirus (CMV) and Epstein-Barr virus ( EBV ). HSV-I, -2, HHV-6, CMV or EBV was not detected in any of the CSF's in this study. Testing for HHV-8 resulted in several products, the specificity of which needs to be confirmed by Southern blotting. This study does not rule out the possibility that herpesviruses are present in the brains of the affected individuals, although the target viral sequences could not be detected in the CSF. Viruses, not identical to prototype herpesviruses, may also be present in the CSF and/or brains of these patients. We are currently also applying a pan-retrovirus PCR detection system (Perron et al.) for screening these same CSF's as well as tissue from the frontal cortex of brains from affected

We have investigated the hypothesis that the expression of brain RNAs may be altered in schizophrenia and bipolar disorder. A modified version of the arbitrarily primedpolymerase chain reaction (AP-PCR) method (Welsh et al.) was used to determine whether RNAs are differentially expressed in cortical regions obtained post-mortem from an individual with schizophrenia and an unaffected individual. Several RNA transcripts had higher expression levels in the frontal cortex of an individual with schizophrenia compared to the normal control. One of the candidate RNAs displayed 77% amino acid homology to the Pol polyprotein of simian retrovirus (SRV)-I, which is a primate type-D retrovirus. A second transcript was nearly identical to the DB~ zinc finger protein ( > 99'7o predicted amino acid similarity), which interacts with the tax protein of human T-cell leukemia virus to increase interleukin-3 transcription. These candidate clones were then screened for disease specificity using (oligo dT-primed) semi-quantitative reverse transcription-PCR on frontal cortical RNAs extracted post-mortem from individuals with schizophrenia i n = 17), bipolar disorder 01- 17), non-psychotic depression ( n - 12), Huntington's Disease ( n - 8 ) and normal controls (n= 15). These reactions were duplexed with a second PCR using primers for glyceraldehyde-3-phosphate dehydrogenase, which is a housekeeping gene, and is used to normalize RNA content across samples. Preliminary data indicate that SRV-like transcript levels are significantly increased in the bipolar group (p<0.004). Our preliminary findings indicate that viral and virus-associated RNA transcripts are expressed in the brains of some individuals with schizophrenia and bipolar disorder, and may play an important role in disease pathogenesis.

Rc/~'rence Welsh eI al. (1992) Nucl Acids Res, 20, 4965.