Upstream eventDecreased, Calcium influx
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities||non-adjacent||Low|
|Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development leads to neurodegeneration with impairment in learning and memory in aging||adjacent||High|
Life Stage Applicability
Key Event Relationship Description
Mainly, NMDA receptor activation initiates Ca2+-dependent signaling events that regulate the expression of genes involved in regulation of neuronal function including bdnf (reviewed in Cohen and Greenberg, 2008). Inhibition of NMDA receptors results in low levels of Ca2+ and decreased transcription of BDNF and consequently to low level of BDNF protein production and release.
Evidence Supporting this KER
BDNF transcription is induced by Ca2+ entering through either L type voltage gated calcium channel (L-VGCC) (Tao et al., 1998) or NMDA receptor (Tabuchi et al., 2000; Zheng et al., 2011) that can last up to 6 h. BDNF IV that is the most studied among its different exons has been shown to bind three Ca2+ elements within the regulatory region (reviewed in Zheng et al., 2012). One of these Ca2+ elements binds to CREB facilitating transcription. However, more transcription factors rather than only CREB are implicated in the transcription process of BDNF such as NFAT (nuclear factor of activated T cell), MEF2 (myocyte enhancer factor 2) and NFκB (nuclear factor κB) (reviewed in Zheng et al., 2012). The activation of the relevant transcription factor is triggered by the initial activation of CaM kinase, cAMP/PKA and Ras/ERK1/2 pathways mediated by the elevated intracellular Ca2+. Interestingly, inhibitory studies targeting different elements of these pathways report reduction at mRNA BDNF levels (reviewed in Zheng et al., 2012).
In particular, exon IV BDNF mRNA transcription is regulated by a transcriptional silencer, methyl-CpG binding protein 2 (MeCP2), demonstrating that epigenetic alterations can also regulate BDNF transcription. Increase of intracellular Ca2+ levels phosphorylates MeCP2, which inactivates its repressor function and permits the transcription of BDNF exon IV (Chen et al., 2003; Greer and Greenberg, 2008; Tao et al., 2009; Zhou et al., 2006). Indeed, NMDA receptor activation has been shown to upregulate BDNF transcripts containing exon IV not only via Ca2+-dependent CREB but also through Ca2+ activation of MeCP2 transcription (Metsis et al., 1993; Shieh et al., 1998, Tao et al., 1998; Tabuchi et al., 2000; Chen et al., 2003; Jiang et al., 2005; Zheng et al., 2011), whereas NMDAR antagonists decrease BDNF exon IV expression (Zafra et al., 1991; Stansfield et al., 2012). Furthermore, BDNF mRNA is also targeted in different locations within the cell during the process of translation, depending on the promoter used (reviewed in Tongiorgi et al., 2006).
Interestingly, synaptic and extra-synaptic NMDARs have opposite effects on CREB: indeed calcium entry through synaptic NMDAR induced CREB activity and BDNF gene expression. In contrast, calcium entry through extra-synaptic NMDAR activates a general and dominant CREB shut-off pathway that blocked induction of BDNF expression (Hardingham et al., 2002).
Include consideration of temporal concordance here
There is no direct evidence linking reduced levels of Ca2+ to decreased BDNF levels as they have not been ever measured both in the same study after exposure to stressors. However, there are findings that strongly link the different elements of Ca2+-dependent signalling events to transcription of BDNF.
Pb2+: Pb2+ decreases the ratio of phosphorylated versus total MeCP2 and consequently MeCP2 maintains its repressor function and prevents BDNF exon IV transcription (Stansfield et al., 2012). MeCP2 gene expression in the frontal cortex is very sensitive to Pb2+ exposure while in the hippocampus, the same gene is affected only at the higher exposure group in rat pups with blood Pb2+ levels 5.8 to 10.3 μg/dl on PND 55 (Schneider et al., 2012). In two different in vivo studies from the same research group, the use of doses of Pb2+ that result in learning and LTP deficits in rats causes decrease in phosphorylation of CREB in cerebral cortex at 14 PND and the same reduction in phosphorylation state of CREB in both cortex and hippocampus at PND 50 (Toscano et al., 2002; 2003). Interestingly, under similar experimental conditions no alteration at the phosphorylation state of CAMKII has been recorded (Toscano et al., 2005). In primary hippocampal neurons exposed to 1 μM Pb2+ for 5 days during the period of synaptogenesis (DIV7–DIV12), both the cellular and extracellular proBDNF protein levels of mBDNF decrease with the latter to smaller extend (Neal et al., 2010). In the same in vitro model, Pb2+ also decreases dendritic proBDNF protein levels throughout the length of the dendrites and causes impairment of BDNF vesicle transport to sites of release in dendritic spines (Stansfield et al., 2012). Furthermore, Pb2+ treatment resulted in a specific reduction of Bdnf exon IV and IX mRNA transcripts causing no alteration in the expression of exons I and II (Stansfield et al., 2012). Rat pups on PND 25 exposed to Pb2+ (180 and 375-ppm lead acetate in food for 30 days) demonstrated blood Pb2+ levels 5.8 to 10.3 μg/dl on PND 55 and show no change at gene levels of BDNF (Schneider et al., 2012). In mouse embryonic stem cells (ESCs), Bdnf exon IV has been found to be down-regulated in cells treated with 0.1 µM Pb, whereas Bdnf exon IX has been found up-regulated (Sánchez-Martín et al., 2013).
Uncertainties and Inconsistencies
In a gene expression study, where gene analysis has been performed in the hippocampus derived from male or female rats fed with 1500 ppm Pb2+-containing chow for 30 days beginning at weaning, two molecular networks have been identified that were different between male and female treated rats. In these networks, CREB was the highly connected node, common for both networks (Schneider et al., 2011). However, no change has been reported in the expression of bdnf gene neither in male nor in female rats treated with Pb2+ (Schneider et al., 2011).
Quantitative Understanding of the Linkage
Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?
No enough data is available to address the questions above.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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