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Relationship: 3300

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

Loss of drebrin leads to Impairment, Learning and memory

Upstream event

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

Loss of drebrin

Downstream event

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

Impairment, Learning and memory

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
Binding of chemicals to ionotropic glutamate receptors leads to impairment of learning and memory via loss of drebrin from dendritic spines of neurons	non-adjacent	High	High	Shihori Tanabe (send email)	Under development: Not open for comment. Do not cite	Under Development

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, rat, mouse	Human, rat, mouse	High	NCBI

Sex Applicability

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

Sex	Evidence
Mixed	Not Specified

Life Stage Applicability

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

Term	Evidence
During development and at adulthood	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

Loss of drebrin disrupts dendritic spine morphology and impairs synaptic plasticity, leading to deficits in learning and memory. Experimental evidence demonstrates that drebrin reduction, achieved either through genetic deletion (up to 80–90%) or antisense knockdown, results in decreased spine density and increased spine length in hippocampal neurons. These structural abnormalities coincide with functional impairments, including reduced hippocampal synaptic plasticity, disrupted regulation of NMDA receptors or associated receptor complexes, and enhanced mGluR5-dependent long-term depression. Animal studies consistently link these molecular and cellular changes to impaired fear learning, spatial memory, and broader cognitive functions.

Implicitly, these findings suggest that drebrin is essential for maintaining proper neuronal circuitry and synaptic integrity, and that its depletion may broadly compromise neuronal network functionality and cognitive processing, even though such broader implications are not explicitly detailed in the original description of key events.

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

Search terms: drebrin, dendreitic spines, cofnitive impairment, learning and memory, Alzheimer's disease model, genetic manipulation. Cmbination two or three terms if too many references are found.

Search Period: No time restrictions applied.

Data base: Our reference libraliy for drebrin which based on PubMed search.

Used AI assistants :Chat GTP-4.5, Consensus and Elicit

Evidence Supporting this KER

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

Our researches

Yamazaki R et al. Studies involving manipulation of drebrin expression (antisense knockdown)

Reni Radiology

Kojima

Yasuda

Others

Counts

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

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

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

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

Drebrin loss is observed in the early stages of Alzheimer disease, even before the formation of amyloid plaques and neurofibrillary tangles, making it a potential early marker for the disease. Drebrin loss contributes significantly to memory impairment by disrupting synaptic plasticity and structure.

Clinical ocservational study which hightly cited:

Counts, S., He, B., Nadeem, M., Wuu, J., Scheff, S., & Mufson, E. (2012). Hippocampal Drebrin Loss in Mild Cognitive Impairment. Neurodegenerative Diseases, 10, 216 - 219. https://doi.org/10.1159/000333122.

Harigaya, Y., Shoji, M., Shirao, T., & Hirai, S. (1996). Disappearance of actin‐binding protein, drebrin, from hippocampal synapses in alzheimer's disease. Journal of Neuroscience Research, 43. https://doi.org/10.1002/JNR.490430111.

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