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Relationship: 347

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Decreased, Calcium influx leads to BDNF, Reduced

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Decreased, Calcium influx

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

BDNF, Reduced

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
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	Low		Florianne Tschudi-Monnet (send email)	Open for citation & comment	WPHA/WNT Endorsed
Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities	adjacent	Low	Low	Anna Price (send email)	Open for citation & comment	WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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 Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

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).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

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

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

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.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

References

List of the literature that was cited for this KER description. More help

Chen WG, Chang Q, Lin Y, Meissner A, West AE, Griffith EC, Jaenisch R, Greenberg ME. (2003) Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science. 302: 885-889.

Cohen S, Greenberg ME. (2008) Communication between the synapse and the nucleus in neuronal development, plasticity and disease. Annu Rev Cell Dev Biol. 24: 183-209.

Greer PL, Greenberg ME. (2008) From synapse to nucleus: Calcium-dependent gene transcription in the control of synapse development and function. Neuron 59: 846-860.

Hardingham GE, Bading H. 2002. Coupling of extrasynaptic NMDA receptors to a CREB shut-off pathway is developmentally regulated. Biochim Biophys Acta 1600(1-2): 148-153.

Heaton MB, Mitchell JJ, Paiva M. (1999) Ethanol-induced alterations in neurotrophin expression in developing cerebellum: relationship to periods of temporal susceptibility. Alcohol Clin Exp Res. 23: 1637-1642.

Jiang X, Tian F, Mearow K, Okagaki P, Lipsky RH, Marini AM. (2005) The excitoprotective effect of N-methyl-D-aspartate receptors is mediated by a brain-derived neurotrophic factor autocrine loop in cultured hippocampal neurons. J Neurochem. 94: 713-722.

Metsis M, Timmusk T, Arenas E, Persson H. (1993) Differential usage of multiple brain-derived neurotrophic factor promoters in the rat brain following neuronal activation. Proc Natl Acad. Sci USA. 90: 8802-8806.

Neal AP, Stansfield KH, Worley PF, Thompson RE, Guilarte TR. (2010) Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: Potential role of NMDA receptor-dependent BDNF signaling. Toxicol Sci. 116: 249-263.

Sánchez-Martín FJ, Fan Y, Lindquist DM, Xia Y, Puga A. (2013) Lead Induces Similar Gene Expression Changes in Brains of Gestationally Exposed Adult Mice and in Neurons Differentiated from Mouse Embryonic Stem Cells. PLoS One 8: e80558.

Schneider JS, Anderson DW, Sonnenahalli H, Vadigepalli R. (2011) Sex-based differences in gene expression in hippocampus following postnatal lead exposure. Toxicol Appl Pharmacol. 256: 179-190.

Schneider JS, Mettil W, Anderson DW. (2012). Differential Effect of Postnatal Lead Exposure on Gene Expression in the Hippocampus and Frontal Cortex. J Mol Neurosci. 47: 76-88.

Shieh PB, Hu SC, Bobb K, Timmusk T, Ghosh A. (1998) Identification of a signaling pathway involved in calcium regulation of BDNF expression. Neuron 20: 727–740.

Stansfield KH, Pilsner JR, Lu Q, Wright RO, Guilarte TR. (2012) Dysregulation of BDNF-TrkB signaling in developing hippocampal neurons by Pb(2+): implications for an environmental basis of neurodevelopmental disorders. Toxicol Sci. 127: 277-295.

Tabuchi A, Nakaoka R, Amano K, Yukimine M, Andoh T, Kuraishi Y and Tsuda M. (2000) Differential activation of brain-derived neurotrophic factor gene promoters I and III by Ca2+ signals evoked via L-type voltage-dependent and N-methyl-D-aspartate receptor Ca2+ channels. J Biol Chem. 275: 17269-17275.Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME. (1998) Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 20: 709-726.

Tao J, Hu K, Chang Q, Wu H, Sherman NE, Martinowich K, Klose RJ, Schanen C, Jaenisch R, Wang W, et al. (2009) Phosphorylation of MeCP2 at Serine 80 regulates its chromatin association and neurological function. Proc Natl Acad Sci USA. 106: 4882-4887.

Tongiorgi E, Domenici L, Simonato M. (2006) What is the biological significance of BDNF mRNA targeting in the dendrites? Clues from epilepsy and cortical development. Mol Neurobiol. 33: 17-32.

Toscano CD, Hashemzadeh-Gargari H, McGlothan JL, Guilarte TR. (2002) Developmental Pb2+ exposure alters NMDAR subtypes and reduces CREB phosphorylation in the rat brain. Brain Res Dev Brain Res. 139: 217-226.

Toscano CD, McGlothan JL, Guilarte TR. (2003) Lead exposure alters cyclic-AMP response element binding protein phosphorylation and binding activity in the developing rat brain. Brain Res. Dev. Brain Res. 145: 219-228.

Toscano CD, O'Callaghan JP, Guilarte TR. (2005) Calcium/calmodulin-dependent protein kinase II activity and expression are altered in the hippocampus of Pb2+-exposed rats. Brain Res. 1044: 51–58.

Zafra F, Castrén E, Thoenen H, Lindholm D. (1991) Interplay between glutamate and gamma-aminobutyric acid transmitter systems in the physiological regulation of brain-derived neurotrophic factor and nerve growth factor synthesis in hippocampal neurons. Proc Natl Acad Sci U S A. 88: 10037-10041.

Zheng F, Zhou X, Luo Y, Xiao H, Wayman G, Wang H. (2011) Regulation of brain-derived neurotrophic factor exon IV transcription through calcium responsive elements in cortical neurons. PLoS One 6: e28441.

Zheng F, Zhou X, Moon C, Wang H. (2012) Regulation of brain-derived neurotrophic factor expression in neurons. In J Pathophysiol Pharmacol 4: 188-200.

Zhou Z, Hong EJ, Cohen S, Zhao WN, Ho HY, Schmidt L, Chen WG, Lin Y, Savner E, Griffith EC, et al. (2006) Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 52: 255-269.