NMDA-mediated and self-induced bdnf exon IV transcriptions are differentially regulated in cultured cortical neurons

Abstract

Activity-dependent transcriptional up-regulation of bdnf (brain-derived neurotrophic factor) is involved in regulating many aspects of neuronal functions. The NMDA (N-methyl-D-aspartic acid)-mediated and BDNF-mediated exon IV transcription may represent mechanistically different responses, and relevant to activity-dependent changes in neurons. We found that the activities of ERK (extracellular signal-regulated kinase), CaM KII/IV (calmodulin-dependent protein kinase II and IV), PI3K (phosphoinositide 3-kinase), and PLC (phospholipase C) are required for NMDA receptor-mediated bdnf exon IV transcription in cultured cortical neurons. In contrast, the BDNFinduced and TrkB-dependent exon IV transcription was regulated by ERK and CaM KII/IV, but not by PI3K and PLC. While ERK and CaM KII/IV are separate signaling pathways in BDNF-stimulated neurons, CaM KII/IV appeared to regulate exon IV transcription through ERK in NMDA-stimulated neurons. Similarly, the PI3K and PLC signaling pathways converged on ERK in NMDA-but not BDNF-stimulated neurons. Our results implicate that the NMDA-induced and the self-maintenance of bdnf transcription are differentially regulated.

AP-1 Transcription Factors Mediate BDNF-Positive Feedback Loop in Cortical Neurons

“…BDNF binds to two distinctive classes of receptors, receptor tyrosine kinase subfamily member TrkB and tumor necrosis factor receptor superfamily member p75 NTR , with mature BDNF preferentially binding to the TrkB receptor and proBDNF to the p75 NTR receptor (Lu et al, 2005). During development, BDNF functions as a differentiation and survival factor for various populations of neurons in the peripheral nervous system and CNS, strictly regulating the number of neurons needed for proper functioning of the nervous system (Bibel and Barde, 2000;Huang and Reichardt, 2001;Park and Poo, 2013). In the adult brain, BDNF has an important role in long-term potentiation (LTP) and memory formation (for review, see Park and Poo, 2013).…”

“…During development, BDNF functions as a differentiation and survival factor for various populations of neurons in the peripheral nervous system and CNS, strictly regulating the number of neurons needed for proper functioning of the nervous system (Bibel and Barde, 2000;Huang and Reichardt, 2001;Park and Poo, 2013). In the adult brain, BDNF has an important role in long-term potentiation (LTP) and memory formation (for review, see Park and Poo, 2013). Dysregulation of BDNF expression is implicated in various neuropsychiatric disorders, indicating the importance of BDNF in higher cognitive functions and mood regulation (for review, see Autry and Monteggia, 2012).…”

“…BDNF has a complex gene structure (Timmusk et al, 1993), with the rodent BDNF gene consisting of one protein-coding 3Ј exon that is spliced together with one of the eight noncoding 5Ј exons . In humans, two additional exons (Vh and VIIIh) have been described (Pruunsild et al, 2007).…”

“…In humans, two additional exons (Vh and VIIIh) have been described (Pruunsild et al, 2007). Each of the 5Ј exons, except the human cassette exons VIII, VIIIh, and IXb, has its own promoter, allowing complex spatiotemporal regulation of BDNF expression in different brain regions and peripheral tissues throughout development Pruunsild et al, 2007) and in response to various stimuli (Metsis et al, 1993;Karpova et al, 2010;Salerno et al, 2012;Baj et al, 2013).…”

“…AP-1 transcription factors preferentially bind to the AP-1 element (also known as TRE, TPA-response element), with consensus sequence TGAC/GTCA (Eferl and Wagner, 2003). As with other basic leucine zipper domain-containing transcription factors, AP-1 proteins can bind DNA only as dimers, and binding to DNA greatly increases the dimer stability (Patel et al, 1994). Whereas Fos family proteins FosB,Fra1,Fra2) are unable to form homodimers (Halazonetis et al, 1988;Shaulian and Karin, 2001), members of the Jun family (c-Jun, JunB, JunD) are able to form both homodimers and heterodimers within the family, and heterodimers with Fos family proteins or with other transcription factors, such as members of the ATF family, C/EBP, and others (Herdegen and Leah, 1998;Chinenov and Kerppola, 2001).…”