Mitogen-activated protein kinases in schizophrenia

Background: Mitogen-activated protein kinases (MAPKs) are important mediato rs of signal transduction from the cell surface to the nucleus and have bee n implicated in the integration of a variety of physiologic processes in mo st cells, including neurons. To investigate the possible involvement of MAP Ks in schizophrenia, we compared the levels of the MAPK intermediates in po stmortem brain tissue obtained from schizophrenic and control subjects. Our focus was on the cerebellar vermis because of evidence suggesting that sch izophrenia is associated with abnormalities of structure, function, and sig nal transduction in this brain region. Methods: Cytosolic proteins were fractionated by gel electrophoresis and su bjected to Western blot analysis using polyclonal MAPK antibody, which dete cts total extracellular signal-regulated kinases (ERKs) 1 and 2 levels, and monoclonal MAP kinase phosphatase (MKP) 2 antibody. Results: Schizophrenic subjects had increased levels of ERK2 [2763 +/- (SD) 203 vs. 2286 +/- 607 arbitrary units, U = 17, p < .05] in cerebellar vermi s. The levels of a dual specificity tyrosine phosphatase, MKP2, were signif icantly decreased in cerebellar vermis (1716 +/- 465 versus 2372 +/- 429 ar bitrary units, U = 12, p < .02) from schizophrenic patients. ERK1/MKP2 and ERK2/2MKP2 ratios in cerebellar vermis, but not in other brain regions, wer e significantly different in schizophrenic subjects as compared to control subjects (U = 15, p less than or equal to .027; U = 3, p < .001, respective ly). Conclusions: MAPK levels are elevated in the cerebellar vermis of schizophr enic subjects. This could result from a protein dephosphorylation defect in vivo and might be involved in the pathology of the disease. Biol Psychiatr y 1999;46:689-696 (C) 1999 Society of Biological Psychiatry.