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Relationship: 354

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

BDNF, Reduced leads to Reduced, Presynaptic release of glutamate

Upstream event

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

BDNF, Reduced

Downstream event

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

Reduced, Presynaptic release of glutamate

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 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

BDNF, acting via its specific presynaptic receptor TrkB, has been shown to increase excitatory synaptic transmission by triggering presynaptic glutamate release in hippocampal cultures as well as in hippocampal and cortical slices (Lessmann et al., 1994; Kang and Schuman, 1995; Carmignoto et al., 1997; Mohajerani et al., 2007).

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

Experimentally, it has been shown that presynaptically, BDNF enhances glutamate release and increases the frequency of mEPSCs in hippocampal neurons of rat (Lessmann and Heumann, 1998; Takei et al., 1998; Minichiello, 2009). It has been reported that BDNF rapidly induces glutamate transporter-mediated glutamate release via phospholipase C-γ (PLC-γ)/Ca2+ signaling and that antidepressants enhance PLC-γ/Ca2+ signaling leading to reduced levels of BDNF that cause decreased glutamate release (Numakawa et al., 2002; Yagasaki et al., 2006).

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

In cortical cultured neurons obtained from PND 2-3 rat pups, BDNF fails to induce glutamate release at DIV 3 and 4. However, after 5 days in vitro culture or more (DIV 6-9), BDNF (100 ng/ml) induces significant glutamate release (2-2.8 fold) within 1 min after exogenous application (Numakawa et al., 2002).

It has been shown that there is a dose-dependent effect of BDNF on the glutamate release. The glutamate release is initially observed at 5 ng/ml BDNF and reaches a plateau at 100 ng/ml (Numakawa et al., 2002).

No studies have been found in the literature measuring both KEs after exposure to the stressors. Interestingly, proton magnetic resonance spectroscopy in adults with childhood lead exposure shows decrease in a composite of glutamate and glutamine in vermis and in parietal white matter of the brain (Cecil et al., 2011).

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

Recently, in heterozygous BDNF-knockout (BDNF+/−) mice it has been demonstrated that the reduced BDNF levels did not affect presynaptic glutamate release (Meis et al., 2012).

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

Carmignoto G, Pizzorusso T, Tia S, Vicini S. (1997) Brain-derived neurotrophic factor and nerve growth factor potentiate excitatory synaptic transmission in the rat visual cortex. J Physiol. 498: 153-164.

Cecil KM, Dietrich KN, Altaye M, Egelhoff JC, Lindquist DM, Brubaker CJ, Lanphear BP. (2011) Proton magnetic resonance spectroscopy in adults with childhood lead exposure. Environ Health Perspect. 119: 403-408.

Kang H, Schuman EM. (1995) Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science. 267: 1658-1662.

Lessmann V, Gottmann K, Heumann R. (1994) BDNF and NT-4/5 enhance glutamatergic synaptic transmission in cultured hippocampal neurones. Neuroreport 6: 21-25.

Lessmann V, Heumann R. (1998) Modulation of unitary glutamatergic synapses by neurotrophin-4/5 or brain-derived neurotrophic factor in hippocampal microcultures: presynaptic enhancement depends on pre-established paired-pulse facilitation. Neuroscience 86: 399-413.

Meis S, Endres T, Lessmann V. (2012) Postsynaptic BDNF signalling regulates long-term potentiation at thalamo-amygdala afferents. J Physiol. 590: 193-208.

Minichiello L. (2009) TrkB signalling pathways in LTP and learning. Nat Rev Neurosci. 10: 850-860.

Mohajerani MH, Sivakumaran S, Zacchi P, Aguilera P, Cherubini E. (2007) Correlated network activity enhances synaptic efficacy via BDNF and the ERK pathway at immature CA3 CA1 connections in the hippocampus. Proc Natl Acad Sci U S A. 104: 13176-13181.

Numakawa T, Yamagishi S, Adachi N, Matsumoto T, Yokomaku D, Yamada M, Hatanaka H. (2002) Brain-derived neurotrophic factor-induced potentiation of Ca2+ oscillations in developing J Biol Chem. 277: 6520-6529.

Takei N, Numakawa T, Kozaki S, Sakai N, Endo Y, Takahashi M, et al. (1998) Brain-derived neurotrophic factor induces rapid and transient release of glutamate through the non-exocytotic pathway from cortical neurons. J Biol Chem. 273: 27620-27624.

Yagasaki Y, Numakawa T, Kumamaru E, Hayashi T, Su TP, Kunugi H. (2006) Chronic antidepressants potentiate via sigma-1 receptors the brain-derived neurotrophic factor-induced signaling for glutamate release. J Biol Chem. 281: 12941-12949.