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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online August 1, 2003 as doi:10.1096/fj.03-0104fje. |
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7 nicotinic acetylcholine receptor in schizophrenia: decreased mRNA levels in peripheral blood lymphocytes1
,
* Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel; and
Beer Yaakov Mental Health Center and
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
2Correspondence: Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel. E-mail: sara.fuchs{at}weizmann.ac.il
SPECIFIC AIMS
Schizophrenia is a neuropsychiatric disorder that affects about 1% of the population worldwide. The precise pathophyisiology of schizophrenia is still not known, though it is accepted that it involves CNS alterations in neurotransmitters and their receptors. To date, there are no reliable peripheral markers for schizophrenia and its diagnosis relies mainly on descriptive behavioral and symptomatic information. Thus, there is a need to develop convenient biological assays for the identification, evaluation, and follow-up of schizophrenia during treatment and to elucidate the molecular basis of this disease. In our laboratory we are investigating human peripheral blood lymphocytes (PBLs), as they have been found to express receptors for several neurotransmitters and it has been suggested that such peripheral receptors may reflect the respective brain receptors. Recent studies indicate an association of the neuronal 
7 nicotinic acetylcholine receptor (7 AChR) with several aspects of schizophrenia, and decreased levels of this receptor in postmortem brains of schizophrenic patients have been reported. In view of that and in search of peripheral markers for schizophrenia, our aim in the present study was to find out whether there is a correlation between schizophrenia and peripheral 7 AChR by analyzing the levels of 7 AChR mRNA in PBLs. Such a correlation substantiates the involvement of 7 AChR in the pathophysiology of schizophrenia and proposes the assay of 7 AChR mRNA levels in PBLs as a potential peripheral biological marker for this illness.
PRINCIPAL FINDINGS
1. mRNA levels of 7 AChR are significantly lower in schizophrenic patients than in healthy controls
Thirty-four patients participated in this study, (14 male and 20 female, age range 18–67 years). Of the 34 patients, 20 were diagnosed schizophrenic patients with chronic illness and 14 were unmedicated schizophrenic patients examined during their first episode of psychosis; in addition, 21 healthy controls were studied, 11 nonsmokers, and 10 smokers, (8 male and 13 female, age range 31–62 years). mRNA levels of 7 AChR in PBL of schizophrenic patients were determined and compared with their levels in lymphocytes of healthy controls.
Lymphocytes were separated from blood samples, total RNA was isolated, and RT-PCR analysis was performed using specific primers for 7 AChR and ß-actin as a control gene. The signals for 7 AChR were significantly lower in schizophrenic patients than in healthy controls. Quantification of the intensities of the specific 7 and ß-actin bands was performed by densitometry. For each individual a relative amount of the level of 7 AChR mRNA was calculated by the ratio of the density value for 7 AChR to the density value for ß-actin (Fig. 1
). Average values were 0.88 ± 0.18, 0.36 ± 0.3, and 0.34 ± 0.26 for healthy controls, schizophrenic medicated patients, and schizophrenic unmedicated patients (during their first episode of psychosis), respectively, demonstrating a significant decrease (P<0.004) in 7 mRNA of schizophrenic patients compared with healthy controls. There was no significant difference between medicated and unmedicated schizophrenic patients.
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The reduction (in percent) in the level of 7 mRNA observed in schizophrenic patients was calculated according to the equation:
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in which 7S/ß-actinS represents the relative amount of 7 for a schizophrenic patient and 7H/ß-actinH represents this value for the healthy control used in the experiment. In experiments in which more than one healthy control was used, the ratio 7H/ß-actinH represents the average of all controls used. There were only six patients (two medicated and four unmedicated), in which the % decrease was <20%. All other patients exhibited a decrease in the 7 mRNA levels ranging from 20% to 92%.
2. The observed decrease in 7 mRNA levels is not a result of nicotine consumption in smoking
To prevent the possible confound of nicotine use in smoking, we investigated whether smoking itself has an effect on 7 mRNA levels. Since all schizophrenic patients in our study smoke, we compared healthy smokers to nonsmokers. The 7/ß-actin ratios for 10 healthy smokers and 8 nonsmokers demonstrate similar average values of 0.83 ± 0.10 and 0.89 ± 0.10, respectively (Fig. 2
), indicating that the decreases in 7 mRNA levels in schizophrenic patients are most likely not a result of smoking.
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CONCLUSIONS AND SIGNIFICANCE
The results of our study demonstrate that schizophrenic patients express lower levels of 7 AChR mRNA in their PBLs than healthy controls. This is in accordance with available reports on a deficit in 7 AChR in postmortem brains in schizophrenia. No significant difference in the levels of 7 mRNA has been observed between medicated schizophrenic patients with chronic illness and unmedicated schizophrenic patients examined during their first episode of psychosis. Thus, the decreased 7 mRNA levels in PBL in schizophrenia may possibly reflect the deficit in this receptor in the brain observed in this disease, and 7 mRNA might be used as a reliable peripheral marker for schizophrenia.
It is interesting that the incidence of smoking in schizophrenia is threefold higher than in the general population. While there exists no evidence for receptor differences between smokers and nonsmokers in the general population, it may be suggested that nicotine use in smoking may influence the levels of 7 AChR. However, our investigation of the effect of smoking on 7 mRNA levels in healthy controls suggests that the decrease in 7 levels in schizophrenic patients is not a result of smoking.
The dopaminergic hypothesis of schizophrenia proposes that hyperactivity of dopamine neurotransmission is responsible for the symptoms of this disorder. In a previous report by our group, in keeping with our attempts to identify biological markers for schizophrenia that can be analyzed in peripheral tissues, we have demonstrated increased levels of D3 dopamine receptor mRNA in PBLs of schizophrenic patients compared with levels in healthy controls. The results of our present study propose 7 receptor mRNA as a further potential biological marker for schizophrenia. A group of eight schizophrenic patients was analyzed for both markers. All these patients showed an increase in D3 mRNA (113.90%±36.60%) and a decrease in 7 mRNA (40.0%±19.90%) (unpublished results). The availability of two different biological markers (7 receptor and D3 receptor) that can be tested in PBL makes the evaluation of schizophrenic patients by an objective peripheral blood test seem promising. Moreover, the fact that these two receptor mRNAs change in opposite directions in schizophrenia i.e., gene expression of D3 receptor increases whereas gene expression for 7 AChR decreases in PBLs of schizophrenic patients (thus mimicking the changes in these receptors observed in postmortem brains) enhances the convenience and reliability of these experimental assays.
In conclusion, in this study we demonstrate decreased levels of mRNA of nicotinic 7 acetylcholine receptor in PBLs of schizophrenic patients. These results are consistent with earlier reports demonstrating a decrease in 7 AChR in postmortem brains from schizophrenic patients. If the changes seen in 7 mRNA in PBLs indeed reflect the state of this receptor in the brain, our findings support the data suggesting that a deficit in nicotinic 7 AChR may be involved in the pathophysiology of schizophrenia. Finally, we suggest that the association between decreased levels of 7 mRNA in PBLs and the expression of schizophrenia may come to be used as a biological marker for the illness.
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-0104fje; doi: 10.1096/fj.03-0104fje 
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