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Relationship: 347

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Decreased, Calcium influx leads to BDNF, Reduced

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help

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

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
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 TFHA/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 TFHA/WNT Endorsed

Taxonomic Applicability

Select one or more structured terms 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. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. 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 Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help
Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility 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 (see page 40 of the User Handbook for further information).   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). 

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  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).

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help
Time-scale
This sub-section should be used to provide 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?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help
Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help

References

List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). 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.