Differential Effects of Protein Synthesis Inhibition on the Activity-Dependent Expression of BDNF Transcripts: Evidence for Immediate-Early Gene Responses from Specific Promoters

Abstract

In the adult rat forebrain, brain-derived neurotrophic factor (BDNF) expression is very rapidly induced by neuronal activity, suggesting that this might occur without intervening protein synthesis. The rat BDNF gene has four differentially regulated promoter regions; each gives rise to an mRNA containing a unique 5' exon (I-IV) and a common 3' exon (V) that codes for mature BDNF protein. The present study used exon-specific in situ hybridization and both in vivo and in vitro preparations to determine whether activity induces BDNF as an "immediate-early gene" (IEG) from specific promoter regions and to compare the regulation of BDNF and nerve growth factor (NGF). In cultured hippocampal slices, kainic acid markedly increased pan-BDNF (exon V) and NGF mRNA content; cycloheximide attenuated the effect of kainic acid on both. In vivo stimulation of a paroxysmal afterdischarge increased both pan-BDNF and NGF mRNA levels in the dentate gyrus granule cells; pretreatment with anisomycin modestly attenuated the paroxysmal afterdischarge-induced increase of both transcripts. To determine whether partial drug effects on BDNF expression reflect the differential regulation of transcript species, levels of mRNAs containing exons I-IV were evaluated. A single afterdischarge increased exon I-IV-containing mRNA levels; anisomycin significantly attenuated the increase in exon I- and II-containing mRNAs but had no effect on the increase in exon III- and IV-containing mRNAs. These data show that for mature forebrain neurons, activity induces the expression of BDNF exon III- and IV-containing transcripts as IEG responses.

Acute Stress Responsiveness of the Neurotrophin BDNF in the Rat Hippocampus is Modulated by Chronic Treatment with the Antidepressant Duloxetine

“…Among the major BDNF isoforms expressed in the brain and investigated in this study, we found that exons IV and VI are regulated by acute stress, although their responsiveness is differently affected by chronic antidepressant treatment. The rapid modulation of exons IV and VI is in agreement with the possibility that they might be induced as 'immediate early genes,' without intervening protein synthesis (Lauterborn et al, 1996). Levels of exon IV mRNA were significantly upregulated by stress independently from DLX administration, although the magnitude of this effect is larger in antidepressant-treated rats.…”

Hippocampal Brain-Derived Neurotrophic Factor Expression Following Treatment with Reboxetine, Citalopram, and Physical Exercise

“…Significant increases in exon II expression were also evident following antidepressant/exercise combinations for 7 or 14 days. Consistent with an immediate early gene mode of expression (Lauterborn et al, 1996), hippocampal levels of the exon III variant were enhanced following shortterm treatment only; no changes were evident following chronic treatment (14 days). It should be noted that shortterm exercise/antidepressant combinations (using both reboxetine and citalopram) were particularly effective in elevating the expression of exon III (Figures 1d, 2d and 3d).…”

Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) Is Differentially Induced in Neurons and Astrocytes after Seizures: Evidence for Developmental, Immediate Early Gene, and Lesion Response

“…The TIMP-1 gene also shares with c-fos (Morgan and Curran, 1991) and BDNF (Hughes et al, 1993;Lauterborn et al, 1996) the property of being transcribed as an IEG. Indeed, cycloheximide did not block the KA-mediated induction of TIMP-1 mRNA but did block the induction of Fos protein, indicating that protein synthesis was successfully inhibited, as previously demonstrated in vivo (Jonec and Wasterlain, 1979;Goto et al, 1990;Papas et al, 1992).…”