ACTIVATION OF THE ORNITHINE DECARBOXYLASE-POLYAMINE SYSTEM AND INDUCTION OF C-FOS AND P53 EXPRESSION IN RELATION TO EXCITOTOXIC NEURONAL APOPTOSIS IN NORMAL AND MICROENCEPHALIC RATS

Microencephalic rats obtained by gestational treatment with the DNA al kylating agent methylazoxymethanol, show a remarkable lack of sensitiv ity to excitotoxic neuropathology caused by systemic injections of the convulsant neurotoxin kainic acid. Taking advantage of this, we have studied in these rats, as well as in normal rats, the relationship bet ween the induction of cellular signals supposedly related to cell deat h and the neuronal apoptosis consequent to kainic acid administration. While normal rats responded to the excitatory insult with a large and relatively long lasting increase of the activity of the enzyme ornith ine decarboxylase and of the concentration of putrescine in some brain regions, these alterations were much smaller in microencephalic rats. Expression of c-fos in brain regions sensitive to kainic acid was qui cker but lasted a noticeably shorter time in microencephalic rats as c ompared to normal animals. A profusion of apoptotic neurons, labeled b y an in situ technique, were observed in the olfactory cortex, amygdal a and hippocampus of normal rats injected with kainic acid, in particu lar 48 h and 72 h after drug administration. At corresponding time int ervals and with similar topographic localization, neurons expressing p 53 protein were observed. By contrast, microencephalic rats displayed only in a few cases and in a small number apoptotic neurons in restric ted areas of the ventral hippocampus and entorhinal cortex. Noticeably , in these cases small populations of p53-expressing neurons were also present in the same areas. The present observations clearly show that oncogenes such as c-fos and p53, as well as ornithine decarboxylase w hich behaves as an immediate-early gene in the brain under certain cir cumstances, undergo noticeably lower and/or shorter induction in micro encephalic rats exposed to excitotoxic stimuli. In these rats, therefo re, the cellular signalling pathways studied here and related to excit otoxic sensitivity and committment to cell death are downregulated as a probable consequence of altered brain wiring.