API

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Relationship: 3301

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

Dendritic spine abnormality leads to Dysfunctional synapses

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Dendritic spine abnormality
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Dysfunctional synapses

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 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 Do not cite Under Development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, mouse, rat human, mouse, rat High NCBI
human Homo sapiens High NCBI
rat Rattus norvegicus 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 brain development, adulthood and aging 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

Activity-dependent plasticity of synaptic structure and function is closely regulated by F-actin dynamics within dendritic spines (Matus, 1999, 2000). Dendritic spines are small, actin-rich protrusions extending from neuronal dendrites. They constitute the postsynaptic compartment of most excitatory synapses and serve as major sites for information processing and storage in the brain. Structural changes in dendritic spine morphology, such as alterations in spine shape and size, correlate strongly with the strength of excitatory synaptic connections. These morphological modifications critically depend on remodeling processes within the underlying actin cytoskeleton (Hotulainen et al., 2010). The formation, maintenance, and modulation of dendritic spines are primarily governed by the dynamics of filamentous actin (F-actin), which is tightly regulated through interactions with various actin-binding proteins (ABPs) and postsynaptic signaling molecules (Borovac et al., 2018). Consequently, abnormalities in dendritic spine structure arising from disrupted actin dynamics can lead directly to synaptic dysfunction.

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

PubMed　

key words: Actin in dendritic spines; morphological abnormality of dendritic spines and synaptic dysfunction

Evidence Supporting this KER

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

Chemicals that disrupt the dynamics of the actin cytoskeleton affect synaptic plasticity in a dose-dependent manner.

Cytochalasin D, cytochalasin B, and latrunculin A all impaired the maintenance of LTP induced by brief high-frequency stimulation. (Krucker T et al. 2000)

Latrunculin A:  Inhibition of actin polymerization with latrunculin A impaired late phase of LTP without affecting the initial amplitude and early maintenance of LTP. These observations suggest that mechanisms regulating the spine actin cytoskeleton contribute to the persistence of LTP. (Fukazawa et al. 2003)

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

high

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
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

minites

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

Borovac J, Bosch M, Okamoto K. Regulation of actin dynamics during structural plasticity of dendritic spines: Signaling messengers and actin-binding proteins. Mol Cell Neurosci. 2018 Sep;91:122-130. doi: 10.1016/j.mcn.2018.07.001. Epub 2018 Jul 9. PMID: 30004015.

Matus A. Postsynaptic actin and neuronal plasticity. Curr Opin Neurobiol. 1999 Oct;9(5):561-5. doi: 10.1016/S0959-4388(99)00018-5. PMID: 10508747.

Matus A. Actin-based plasticity in dendritic spines. Science. 2000 Oct 27;290(5492):754-8. doi: 10.1126/science.290.5492.754. PMID: 11052932.

Hotulainen P, Hoogenraad CC. Actin in dendritic spines: connecting dynamics to function. J Cell Biol. 2010 May 17;189(4):619-29. doi: 10.1083/jcb.201003008. Epub 2010 May 10. PMID: 20457765; PMCID: PMC2872912.

Krucker T, Siggins GR, Halpain S. Dynamic actin filaments are required for stable long-term potentiation (LTP) in area CA1 of the hippocampus. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6856-61. doi: 10.1073/pnas.100139797. PMID: 10823894; PMCID: PMC18765.

Fukazawa Y, Saitoh Y, Ozawa F, Ohta Y, Mizuno K, Inokuchi K. Hippocampal LTP is accompanied by enhanced F-actin content within the dendritic spine that is essential for late LTP maintenance in vivo. Neuron. 2003 May 8;38(3):447-60. doi: 10.1016/s0896-6273(03)00206-x. PMID: 12741991.