LITHIUM DECREASES MEMBRANE-ASSOCIATED PROTEIN-KINASE-C IN HIPPOCAMPUS- SELECTIVITY FOR THE ALPHA-ISOZYME

We investigated the effects of lithium on alterations in the amount an d distribution of protein kinase C (PKC) in discrete areas of rat brai n by using [H-3]phorbol 12,13-dibutyrate quantitative autoradiography as well as western blotting. Chronic administration of lithium resulte d in a significant decrease in membrane-associated PKC in several hipp ocampal structures, most notably the subiculum and the CA1 region. In contrast, only modest changes in [H-3]phorbol 12,13-dibutyrate binding were observed in the various other cortical and subcortical structure s examined. Immunoblotting using monoclonal anti-PKC antibodies reveal ed an isozyme-specific 30% decrease in hippocampal membrane-associated PKC alpha, in the absence of any changes in the labeling of either th e beta(I/II) or gamma isozymes. These changes were observed only after chronic (4 week) treatment with lithium, and not after acute (5 days) treatment, suggesting potential clinical relevance. Given the critica l role of PKC in regulating neuronal signal transduction, lithium's ef fects on PKC in the limbic system represent an attractive molecular me chanism for its efficacy in treating both poles of manic-depressive il lness. In addition, the decreased hippocampal membrane-associated PKC observed in the present study offers a possible explanation for lithiu m-induced memo impairment.