DIFFERENTIAL USAGE OF MULTIPLE BRAIN-DERIVED NEUROTROPHIC FACTOR PROMOTERS IN THE RAT-BRAIN FOLLOWING NEURONAL ACTIVATION

The rat brain-derived neurotropic factor (BDNF) gene consists of four 5' exons linked to separate promoters and one 3' exon encoding the pre pro-BDNF protein. To gain insights into the regulation of BDNF mRNA ex pression, probes specific for the different 5' exons were used to stud y the expression of BDNF mRNA in the brain. Following a systemic injec tion of the glutamate analog kainic acid, exon I, II, and III mRNAs in creased transiently in hippocampus and cerebral cortex. A modest incre ase was seen for exon IV, where a new transcription initiation site wa s induced by this treatment. Pretreatments with the N-methyl-D-asparta te (NMDA) receptor antagonist MK801 or the lpha-amino-3-hydroxy-5-meth yl-4-isoxazolepropionic acid (AMPA) receptor antagonist 2,3-dihydroxy- 6-nitrosulfanoylbenzo(f)quinoxaline revealed two region-specific patte rns of glutamate receptor-mediated regulation. The first pattern found in neocortex, piriform cortex, and amygdala involves regulation of BD NF exon I, II, and III mRNAs through NMDA and AMPA/kainate receptors. The second pattern found in the hippocampus involves regulation of BDN F exon I, II, and III mRNAs by high-affinity kainate or metabotropic r eceptors. Treatment with the gamma-aminobutyric acid subtype A (GABA(A )) receptor antagonist bicuculline increased exon I and III mRNAs in t he dentate gyrus, and the muscarinic receptor agonist pilocarpine incr eased exon I mRNA mainly in the neocortex. These data show that the fo ur BDNF promoters allow multiple points of BDNF mRNA regulation and su ggest that the activation of different subtypes of glutamate receptors differentially regulates the expression of BDNF exon-specific mRNAs i n the brain.