Low GSK-3 activity in frontal cortex of schizophrenic patients N. Kozlovsky a , R.H. Belmaker a,b ,G.Agam a,c, * a Stanley Foundation International Research Center, Ben-Gurion University of the Negev, Beersheva, Israel b Ministry of Health Mental Health Center, Ben-Gurion University of the Negev, Beersheva, Israel c Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheva, Israel Received1June2000;accepted11October2000 Abstract Glycogen synthase kinase-3 GSK-3) EC 2.7.1.37) is a protein kinase highly abundant in brain and involved in signal transductioncascadesofmultiplecellularprocesses,particularlyneurodevelopment.Twoformsoftheenzyme,GSK-3a and -3b have been previously identi®ed. We have previously reported reduced GSK-3b protein levels in postmortem frontal cortex of schizophrenic patients. In an attempt to explore whether reduction of GSK-3b levels is brain region speci®c we examineditinoccipitalcortex.Inorderto®ndoutifthereductioninfrontalcortexisre¯ectedinalteredactivitywemeasured GSK-3 enzymatic activity in this brain region. Western-blot analysis of GSK-3b was carried out in postmortem occipital cortex of 15 schizophrenic, 15 bipolar, and 15 unipolar patients, and 15 normal controls. GSK-3 activity was measured by quantitatingthephosphorylationofthespeci®csubstratephospho-CREBinthefrontalcortexspecimens.GSK-3b levelsin occipital cortex did not differ between the four diagnostic groups. GSK-3 activity in the frontal cortex of schizophrenic patientswas45%lowerthanthatofnormalcontrols 0:196 ^ 0:082and0:357 ^ 0:084pmol=mgprotein £ min,respectively; Kruskal±Wallisanalysis:chi-square  8.27, df  3, p  0.04).Theothertwodiagnosticgroupsshowednodifferencefrom the control group. Our results are consistent with the notion that schizophrenia involves neurodevelopmental pathology. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Glycogen synthase kinase-3; Protein levels; Enzyme activity; Postmortem brain; Frontal cortex; Occipital cortex 1. Introduction Theneurodevelopmentalhypothesisofschizophre- nia proposes that orderly brain development is affected by an as yet unidenti®ed event occurring duringpregnancyoratearlypostnatalperiodAltshu- ler et al., 1987; Arnold et al., 1991a; Conrad and Scheibel, 1987). Although the presence of cytoarchi- tecturalabnormalitiesinschizophreniahasbeendocu- mented for review see Weinberger, 1996; Arnold, 1999; Bunney et al., 1995; Chua and Murray, 1996; Hudson et al., 1993) the underlying molecular mechanisms causing these features remain unclear. TheWntfamilyofgenesiscentraltonormalbrain development Cotter et al., 1998). Cell activation by Wnt leads to the inactivation of glycogen synthase kinase-3b GSK-3b).Thisinturnallowstheaccumu- lation of b-catenin, which translocates to the nucleus where it interacts with neuronal transcription factors Moon et al., 1997). Wnt-7a, through GSK-3b, was found to regulate axonal remodeling in developing cerebellar neurons Lucas et al., 1998). There are reports of increased Wnt-1 expression in hippo- campus Miyaoka et al., 1999), and reduced levels SchizophreniaResearch522001)101±105 0920-9964/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII:S0920-996400)00174-2 www.elsevier.com/locate/schres * Corresponding author. Tel.: 1972-7-6401-737; fax: 1972-7- 6401-621. E-mail address: agamg@netvision.net.il G. Agam).