RAPID INCREASE OF BDNF MESSENGER-RNA LEVELS IN CORTICAL-NEURONS FOLLOWING SPREADING DEPRESSION - REGULATION BY GLUTAMATERGIC MECHANISMS INDEPENDENT OF SEIZURE ACTIVITY

Levels of mRNA for nerve growth factor (NGF), brain-derived neurotroph ic factor (BDNF), neurotrophin-3 (NT-3) and the tyrosine kinase recept ors trkB and trkC have been studied using in situ hybridization in the rat brain after topical application of KCl to the cortical surface (w hich induces spreading depression). Repeated episodes of spreading dep ression during 2 h caused a rapid and marked increase of BDNF mRNA lev els in deep and, in particular, superficial cortical layers of the ips ilateral hemisphere (to 213 and 417% of control, respectively). Maxima l levels were reached within 2 h after the cessation of spreading depr ession and at 24 h BDNF mRNA expression had returned to control values . Levels of BDNF mRNA were unaffected in the hippocampus, in areas out side the cerebral cortex and in the contralateral hemisphere. Furtherm ore, no change of the expression of mRNA for NGF, NT-3, trkC or the fu ll length trkB receptor was detected at any time point. However, at 2 h after spreading depression there was an increased level (150% of con trol) in superficial cortical layers of mRNA hybridizing to an oligonu cleotide probe detecting both truncated receptors lacking the tyrosine kinase domain and full length trkB receptors. Also one single episode of spreading depression gave rise to a significant increase of cortic al BDNF mRNA levels (to 207% of control), which was attenuated (by 61% ) after administration of the competitive NMDA receptor antagonist CGS 19755. The results provide evidence that mild brain insults associate d with glutamate release and elevated intracellular calcium, such as s preading depression, also in the absence of seizure activity can lead to activation of the BDNF gene in cortical neurons.