INCREASED PRESYNAPTIC PROTEIN-KINASE-C ACTIVITY AND GLUTAMATE RELEASEIN RATS WITH A PRENATALLY INDUCED HIPPOCAMPAL LESION

We have previously shown that protein kinase C (PKC) activity is up-re gulated in nerve terminals of animals that have been subjected to targ eted cellular ablation of cortical and hippocampal neurons by treatmen t with methylazoxymethanol (MAM), which results in impaired long-term potentiation (LTP) and cognitive deficit. In this study we investigate d the consequences of increased membrane-bound PKC in the regulation o f release of glutamate, the major excitatory transmitter involved in L TP. We show that nerve terminals of MAM-treated rats show higher PKC a ctivity, as monitored by the in situ phosphorylation of B-50/GAP-43, i n both basal and phorbol ester-stimulated conditions. In these animals , hippocampal nerve endings release a greater amount of glutamate than those of controls, both in basal conditions and when synaptosomes are stimulated with KCl or 3,4-diaminopyridine. The potentiation observed in MAM-treated rats was counteracted by the PKC blocker H-7 and the c lostridial tetanus toxin. On the contrary, GABA release was not signif icantly up-regulated, either in basal or in depolarization-evoked cond itions. Therefore our data show that the increase in synaptosomal PKC activity is paralleled by increased glutamate but not GABA release in this animal model. Whether this reflects specific upregulation of memb rane PKC activity in glutamatergic terminals or an alteration in the r egulation of glutamate release remains to be determined.