REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR GENE-EXPRESSION AFTERTRANSIENT MIDDLE CEREBRAL-ARTERY OCCLUSION WITH AND WITHOUT BRAIN-DAMAGE

Levels of mRNA for c-fos, nerve growth factor (NGF), brain-derived neu rotrophic factor (BDNF), neurotrophin-3 (NT-3), TrkB, and TrkC were st udied using in situ hybridization in the rat brain at different reperf usion times after unilateral middle cerebral artery occlusion (MCAO). Short-term (15 min) MCAO, which does not cause neuronal death, induced elevated BDNF mRNA expression confined to ipsilateral frontal and cin gulate cortices outside the ischemic area. With a longer duration of M CAO (2 h), which leads to cortical infarction, the increase was more m arked and elevated BDNF mRNA levels were also detected bilaterally in dentate granule cells and CA1 and CA3 pyramidal neurons. Maximum expre ssion was found after 2 h of reperfusion. At 24 h BDNF mRNA expression had returned to control values. In the ischemic core of the parietal cortex only scattered neurons were expressing high levels of BDNF mRNA after 15 min and 2 h of MCAO. Analysis of different BDNF transcripts showed that MCAO induced a marked increase of exon III mRNA but only s mall increases of exon I and II mRNAs in cortex and hippocampus. In co ntrast to BDNF mRNA, elevated expression of c-fos mRNA was observed in the entire ipsilateral cerebral cortex, including the ischemic core, after both 15 min and 2 h of MCAO. Two hours of MCAO also induced tran sient, bilateral increases of NGF and TrkB mRNA levels and a decrease of NT-3 mRNA expression, confined to dentate granule cells. The upregu lation of BDNF mRNA expression in cortical neurons after MCAO is proba bly triggered by glutamate through a spreading depression-like mechani sm. The lack of response of the BDNF gene in the ischemic core may be due to suppression of signal transduction or transcription factor synt hesis caused by the ischemia. The observed pattern of gene expression after MCAO agrees well with a neuroprotective role of BDNF in cortical neurons. However, elevated levels of NGF and BDNF protein could also increase synaptic efficacy in the postischemic phase, which may promot e epileptogenesis. (C) 1995 Academic Press, Inc.