This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 2411


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

Neuronal network function, Decreased leads to Cognitive Function, Decreased

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). 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

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Organo-Phosphate Chemicals induced inhibition of AChE leading to impaired cognitive function non-adjacent Moderate Moderate Brendan Ferreri-Hanberry (send email) Under development: Not open for comment. Do not cite

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
human Homo sapiens NCBI
rat Rattus norvegicus NCBI
mouse Mus musculus 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

An upstream key event decrease in neuronal network function leads to deficiency of learning and memory which is the sign of cognitive deficits (downstream, adverse outcome) (Anna Bal-Price et al., 2017). Learning and memory- a cognitive function is dependent to neuronal network function. Experimental approach advocates that in hippocampal neurons cognitive-induced enhancement in neuronal excitability, as a measurement of neural network function (Anna Bal-Price et al., 2017; Saar and Barkai, 2003).  Cognitive defect is the functional output of neural networks of mammalian. Exposure to the potential developmental toxicants during neuronal differentiation and synaptogenesis will increase risk of functional neuronal network damage leading to learning and memory impairment ( Cognitive defects like learning and memory are measured using behavioral test. It is well attested that the changes in behavior are the outcome of structural/ functional changes in neuronal network. Functional impairments are typically measured by field potentials of critical synaptic circuits in hippocampus. (Wang et al., 2012; Gilbert et al., 2016).

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

Morris water maze (MWM) test as a means to investigate spatial learning and memory in laboratory rats reveals that the disconnection among neuronal networks  are responsible for the performance impairment of MWM test rather than the damage or injury of certain part of brain . (; D'Hooge and De Deyn, 2001). However, it is well established that alterations in synaptic transmission and plasticity contribute to deficits in cognitive function (

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

One of the major difficult concerns for neuroscientists is to link neuronal network function to cognition, including learning and memory. It is quiet blind that what alterations of neuronal circuits essential to observe change in motor behavior including learning and memory (Mayford et al., 2012), thus there is no any strong evidence defining that how these two KEs are connected ( Thus it’s difficult to establish the direct relationship of alterations in neural network function and specific cognitive deficits due to the complexity of synaptic interactions in even the simplest brain circuit. (

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

A common mechanisms across the taxonomies is working for synaptic transmission and plasticity. Long term synaptic potential has been recorded in aplysia, lizards, turtles, birds, mice, guinea pigs, rabbits and rats (;


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

Anna Bal-Price, Pamela J. Lein, Kimberly P. Keil, Sunjay Sethi, Timothy Shafer, Marta Barenys, Ellen Fritsche, Magdalini Sachana, M.E. (Bette) Meek. Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity, NeuroToxicology, Volume 59, 2017, Pages 240-255, ISSN 0161-813X,

D'Hooge R, De Deyn PP. (2001). Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev. 36: 60-90.

Gilbert ME, Sanchez-Huerta K, Wood C. (2016). Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology 157:774-787.

Mayford M, Siegelbaum SA, Kandel ER. (2012). Synapses and memory storage. Cold Spring Harb Perspect Biol. 4. pii: a005751.

Palop JJ, Mucke L. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat Rev Neurosci. 2016 Dec;17(12):777-792. doi: 10.1038/nrn.2016.141. Epub 2016 Nov 10. PMID: 27829687; PMCID: PMC8162106

Saar, D. and Barkai, E. (2003), Long-term modifications in intrinsic neuronal properties and rule learning in rats. European Journal of Neuroscience, 17: 2727-2734.

Wang S, Teng W, Gao Y, Fan C, Zhang H, Shan Z. (2012). Early levothyroxine treatment on maternal subclinical hypothyroidism improves spatial learning of offspring in rats. J Neuroendocrinol 24:841–848