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Relationship: 870

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 GABAergic interneurons, Decreased

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
GABAergic interneurons, Decreased

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
Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment adjacent Moderate Low Arthur Author (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
Term Scientific Term Evidence Link
rat Rattus norvegicus High NCBI
mouse Mus musculus High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
During brain development High

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

GABAergic interneurons are remarkably diverse and complex in nature and they are believed to play a key role in numerous neurodevelopmental processes (Southwell et al., 2014). Among them, those that express parvalbumin (PV) (marker of GABAergic interneurons) as their calcium-binding protein are the ones subjected to regulations by neurotrophins and BDNF specifically (Woo and Lu, 2006). These neurons do not express the BDNF protein but its functional receptor, Trk-B (Cellerino et al., 1996; Marty et al., 1996; Gorba and Wahle, 1999). BDNF is released by the BDNF-producing neurons of the CNS and binds to Trk-B of the GABA PV-interneurons, an interaction necessary for the subsequent developmental effects mediated by BDNF (Polleux et al., 2002; Jin et al., 2003; Rico et al., 2002; Aguado et al., 2003). BDNF promotes the morphological and neurochemical maturation of hippocampal and neocortical interneurons and promotes GABAergic synaptogenesis (Danglot et al., 2006 and Hu and Russek, 2008). BDNF also regulates the expression of the GABA-specific K(+)/Cl(-) co-transporter, KCC2, which is responsible for switching of GABA action from excitatory to inhibitory, and consequently determines the nature of GABA-induced development of glutamatergic (excitatory) synapses (Wang and Kriegstein, 2009; Blaesse et al., 2009).

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 Map 2.0

ID Experimental Design Species Upstream Observation Downstream Observation Citation (first author, year) Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Title First Author
Biological Plausibility
Dose Concordance
Temporal Concordance
Incidence Concordance
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
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

The role of BDNF on differentiation and maturation of GABAergic interneurons is supported by the studies described in Weight of Evidence section. However, in a recent publication (Puskarjov et al., 2015) BDNF-/- mice were utilized to show that in the absence of BDNF the seizure-induced up regulation of KCC2 was eliminated, but interestingly no change in early (P5-6) or later (P13-14) postnatal KCC2 expression was observed compared to the wild type littermates, but neither the functionality of KCC2 protein was investigated, nor the ability of the neurons to extrude Cl- in the absence of BDNF.

Additionally, other studies have shown that the up-regulation of KCC2 via the transcription factor Egr4 is also regulated by a different neurotrophic factor, neurturin (Ludwig et al., 2011b). These results reveal that the same transcriptional pathways, such as KCC2, can be activated by different neurotrophic factors and might lead to the same outcome under different conditions. This hypothesis should be further investigated, as it could explain the compensation mechanisms that are activated in the total absence of BDNF, and which might be different from those that are triggered by a decrease of BDNF levels.

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

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

Empirical evidence comes from work with laboratory rodents (rats and mice). No data are available for other species.