CHANGES IN PROTEIN-KINASE-C AND ITS PRESYNAPTIC SUBSTRATE B-50 GAP-43AFTER INTRAUTERINE EXPOSURE TO METHYLAZOXY-METHANOL, A TREATMENT INDUCING CORTICAL AND HIPPOCAMPAL DAMAGE AND COGNITIVE DEFICIT IN RATS/

The involvement of protein kinase C (PKC)-dependent processes in adapt ive and plastic changes underlying neuronal plasticity was tested in a n in vivo animal model characterized by targeted cellular ablation of cortical and hippocampal neurons, cognitive impairment and lack of ind uction of long-term potentiation. [H-3]Phorbol ester binding performed on brain slices revealed a 67.4 and 35.0% increase in membrane-bound protein kinase C in the cortex and hippocampus respectively of rats tr eated with methylazoxy-methanol acetate compared with saline-treated c ontrol rats, and there was no modification in the expression of mRNAs of different protein kinase C isozymes. In situ phosphorylation experi ments performed with (32)Pi-labelled synaptosomes from the affected ar eas demonstrated that the phosphorylation of the nervous tissue-specif ic presynaptic membrane-associated protein kinase C substrate B-50/GAP -43 was increased by 51.4 and 44.8% in cortex and hippocampus respecti vely. Western blot analysis of protein kinase C in synaptosomal cytoso l and membrane fractions prepared from cortex and hippocampus showed a n increased proportion of protein kinase C in the membrane compartment in treated animals, but no change in the total synaptosomal protein k inase C activity. Our data are consistent with increased activity of p resynaptic protein kinase C and predict a sustained increase in glutam ate release in methylazoxy-methanol-treated rats.