NMDA RECEPTOR-DEPENDENT AND RECEPTOR-INDEPENDENT IMMEDIATE-EARLY GENE-EXPRESSION INDUCED BY FOCAL MECHANICAL BRAIN INJURY

In the present study we analysed, by in situ hybridization, the effect s of an extremely localized mechanical brain injury, obtained by the s imple needle insertion (30 g) in rat hippocampus or cortex, on the exp ression of several immediate early genes (c-fos, fosB, c-jun, junB, ju nD, zif/268). When the needle is deepened into the hippocampus through the cortex, a simultaneous ipsilateral activation of all examined IEG s is observed in both the cerebral cortex and in the dentate gyrus of hippocampus. Maximal effects are detected between 30 and 60 min with t he following rank order of induction: zif/268 > c-fos-> junB > fosB > c-jun > junD. On the other hand, when the penetration of the needle is limited to the cerebral cortex the activation of the IEGs (c-fos, fos B, junB and zif/268) spreads throughout the ipsilateral cortex but doe s not involve the hippocampal region. Systemic administration of ketam ine, a non-competitive antagonist of N-methyl-D-aspartate (hTMDA) rece ptors, blocks IEG expression induced by brain injury in the cerebral c ortex and in the hippocampal dentate gyrus. Pretreatment with the anti convulsant diazepam, the anaesthetic urethane, or the muscarinic recep tor antagonist scopolamine do not affect the injury-induced genomic re sponse. An important regional difference in the sensitivity to the blo cking effect of ketamine can be observed analysing the results regardi ng the zif/268 gene expression in the hippocampus. A clear induction o f this gene by needle insertion can be detected both in the dentate gy rus and in the hippocampal layers. However, the dentate gyrus inductio n is completely blocked by the ketamine pretreatment, while the induct ion in the hippocampal layers is not affected by this NMDA antagonist. The zif/268 induction in the hippocampal layers is not blocked even i f the intracerebroventricular administration of a non-NMDA glutamate r eceptor antagonist is associated to the systemic pretreatment with ket amine. This result represents the first observation of injury-induced neuronal genomic responses that are not critically dependent on the NM DA receptor activity.