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Svetlana V. Kyosseva, PhD; Alan D. Elbein, PhD; Theron L. Hutton, BS; W. Sue T. Griffin, PhD; Robert E. Mrak, MD, PhD; William Q. Sturner, MD; Craig N. Karson, MD

Arch Gen Psychiatry. 2000;57:685-691.

Background  We investigated the levels of transcription factors associated with activation of the mitogen-activated protein (MAP) kinase pathway in schizophrenics using postmortem brain samples. These studies were done to determine whether our previous findings of abnormal levels of the MAP kinases in the cerebellar vermis were linked to additional downstream targets of this signal transduction pathway.

Method  We measured the protein levels of 3 transcription factors in nuclear fractions of postmortem samples from cerebellar vermis of 10 patients with schizophrenia and 13 control subjects: Elk-1, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and activating transcription factor 2 (ATF-2). Studies in rats examined the postmortem stability and effect of haloperidol and risperidone on levels of Elk-1, cAMP, and ATF-2 proteins.

Results  We found a significant increase in the protein levels of Elk-1 (mean±SD, 4489±659 vs 2915±583 arbitrary densitometric units [P<.001]), CREB (mean±SD, 2149±1061 vs 904±711 arbitrary densitometric units [P=.003]) and ATF-2 (mean±SD, 1421±854 vs 512±394 arbitrary densitometric units [P=.003]) in the cerebellar vermis of schizophrenic subjects. Complementary studies in rats indicate that these findings can not be attributed to subacute treatment with antipsychotic medications.

Conclusion  Taken together with the alterations of MAP kinases previously reported, and the findings of elevations of downstream transcription targets, we suggest that the MAP kinase signal transduction pathway contributes to the cerebellar abnormalities in schizophrenia.

From the Departments of Biochemistry and Molecular Biology (Drs Kyosseva and Elbein and Mr Hutton), Psychiatry (Drs Kyosseva, Griffin, and Karson), and Pathology (Drs Griffin, Mrak, Sturner, and Karson), University of Arkansas for Medical Sciences, the Geriatric Research Education Clinical Center (Dr Griffin) and the Mental Illness Research Education Clinical Center (Drs Griffin and Karson), the Central Arkansas Veterans Healthcare System (Dr Mrak); and the State of Arkansas Medical Examiners Office (Dr Sturner), Little Rock.

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