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Relationship: 2807

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 Dysfunctional synapses

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

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
Various neuronal effects induced by elavl3, sox10, and mbp	adjacent	Moderate	Moderate	Donggon Yoo (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 Do not cite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
Homo sapiens	Homo sapiens	High	NCBI
Rattus norvegicus	Rattus norvegicus	High	NCBI
Mus musculus	Mus musculus	High	NCBI

Sex Applicability

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

Sex	Evidence
Unspecific	High

Life Stage Applicability

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

Term	Evidence
During development and at adulthood	Moderate

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 from dendritic spines impairs the structural and functional integrity of synapses. In animal models and cultured hippocampal neurons, reduced drebrin levels disrupt actin dynamics, leading to decreased dendritic spine density, altered spine morphology, and consequently impaired synaptic function in neuron-neuron interactions. Studies indicate that drebrin loss—whether induced by genetic deletion, antisense oligonucleotides, or Egr-1–mediated downregulation—also restricts microtubule entry into spines and alters receptor complex formation. Reduced spine density and deficits in excitatory transmission were observed. Diminished drebrin disrupts actin- and microtubule-dependent spine organization, compromises postsynaptic protein clustering, and impairs NMDAR function, thereby inducing synaptic dysfunction.

Downregulationof drebrin A expression by antisense oligonucleotides resulted in distuption of PSD-95 clustering andd synaptic integrity (Takahashi, et al. 2003). Drebrin A up-regulation plays a pivotal role in spine morphogenesis and activity-dependent synaptic targeting of NMDA receptors (Takahashi, et al. 2006). Downregulation of drebrin A led to a decrease of both glutamatergic and GABAergic synaptic activity (Ivanov et al., 2009). Level of protein complexes containing dopamine receptor D1/dopamine receptor D2, 5-hydroxytryptamine receptor 1A (5-HT1(A)R), and 5-hydroxytryptamine receptor 7 (5-HT7R) were significantly reduced in hippocampus of drebrin knockout mice (Jung et al. 2015). Drebrin A facilitates the trafficking of NMDAR cargos in an F-actin-dependent manner to mediate homeostatic plasticity (Aoki and Sherpa, 2017). The prolonged intracellular Ca²⁺ increase in dendritic spines of neurons inhibits the re-accumulation of DF-actin, resulting in facilitation of AMPAR endocytosis (Sekino st al. 2017)　

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

Elicit: Drebrin Loss 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

Although normalized SYP and SYT levels were preserved, DRB was reduced by approximately 40% in the hippocampus of MCI and AD compared to NCI subjects (Counts, et al. 2012) Beta-amyloid (Abeta) was directly involved in PAK signaling deficits and drebrin loss in Abeta oligomer-treated hippocampal neurons and in the Appswe transgenic mouse model bearing a double mutation leading to higher Abeta production (Zhao, et al. 2006)

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

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

Downregulationof drebrin A expression by antisense oligonucleotides resulted in distuption of PSD-95 clustering andd synaptic integrity (Takahashi, et al. 2003). Drebrin A up-regulation plays a pivotal role in spine morphogenesis and activity-dependent synaptic targeting of NMDA receptors (Takahashi, et al. 2006) Downregulation of drebrin A led to a decrease of both glutamatergic and GABAergic synaptic activity (Ivanov et al., 2009). Level of protein complexes containing dopamine receptor D1/dopamine receptor D2, 5-hydroxytryptamine receptor 1A (5-HT1(A)R), and 5-hydroxytryptamine receptor 7 (5-HT7R) were significantly reduced in hippocampus of drebrin knockout mice (Jung et al. 2015). Drebrin A facilitates the trafficking of NMDAR cargos in an F-actin-dependent manner to mediate homeostatic plasticity (Aoki and Sherpa, 2017).

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

Modulating Factor (MF)	MF Specification	Effect(s) on the KER	Reference(s)
Egr-1	high	increase	Cho, et al. 2017
beta-amyloid (Abeta)	high	enhanceing	Zhao, et al. 2006

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

Although normalized SYP and SYT levels were preserved, DRB was reduced by approximately 40% in the hippocampus of MCI and AD compared to NCI subjects (Counts, et al. 2012)

An effective expression of drebrin improves cognitive abilities and alleviates lesions in an AD mouse model. (Liu Y, et al. 2017)

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

Antisense oligonucleotides A few days during synaptogenesis (Takahashi, et al 2003)

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

Appearance order

Takahashi H, Sekino Y, Tanaka S, Mizui T, Kishi S, Shirao T. Drebrin-dependent actin clustering in dendritic filopodia governs synaptic targeting of postsynaptic density-95 and dendritic spine morphogenesis. J Neurosci. 2003 Jul 23;23(16):6586-95. doi: 10.1523/JNEUROSCI.23-16-06586.2003. PMID: 12878700; PMCID: PMC6740629.

Takahashi H, Mizui T, Shirao T. Down-regulation of drebrin A expression suppresses synaptic targeting of NMDA receptors in developing hippocampal neurones. J Neurochem. 2006 Apr;97 Suppl 1:110-5. doi: 10.1111/j.1471-4159.2005.03536.x. PMID: 16635259.

Ivanov A, Esclapez M, Pellegrino C, Shirao T, Ferhat L. Drebrin A regulates dendritic spine plasticity and synaptic function in mature cultured hippocampal neurons. J Cell Sci. 2009 Feb 15;122(Pt 4):524-34. doi: 10.1242/jcs.033464. Epub 2009 Jan 27. PMID: 19174472.

Jung G, Kim EJ, Cicvaric A, Sase S, Gröger M, Höger H, Sialana FJ, Berger J, Monje FJ, Lubec G. Drebrin depletion alters neurotransmitter receptor levels in protein complexes, dendritic spine morphogenesis and memory-related synaptic plasticity in the mouse hippocampus. J Neurochem. 2015 Jul;134(2):327-39. doi: 10.1111/jnc.13119. Epub 2015 Apr 29. PMID: 25865831.

Aoki C, Sherpa AD. Making of a Synapse: Recurrent Roles of Drebrin A at Excitatory Synapses Throughout Life. Adv Exp Med Biol. 2017;1006:119-139. doi: 10.1007/978-4-431-56550-5_8. PMID: 28865018.

Sekino Y, Koganezawa N, Mizui T, Shirao T. Role of Drebrin in Synaptic Plasticity. Adv Exp Med Biol. 2017;1006:183-201. doi: 10.1007/978-4-431-56550-5_11. PMID: 28865021.

Counts SE, He B, Nadeem M, Wuu J, Scheff SW, Mufson EJ. Hippocampal drebrin loss in mild cognitive impairment. Neurodegener Dis. 2012;10(1-4):216-9. doi: 10.1159/000333122. Epub 2012 Feb 4. PMID: 22310934; PMCID: PMC3363353.

Cho C, MacDonald R, Shang J, Cho MJ, Chalifour LE, Paudel HK. Early growth response-1-mediated down-regulation of drebrin correlates with loss of dendritic spines. J Neurochem. 2017 Jul;142(1):56-73. doi: 10.1111/jnc.14031. Epub 2017 Apr 26. PMID: 28369888.

Zhao L, Ma QL, Calon F, Harris-White ME, Yang F, Lim GP, Morihara T, Ubeda OJ, Ambegaokar S, Hansen JE, Weisbart RH, Teter B, Frautschy SA, Cole GM. Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nat Neurosci. 2006 Feb;9(2):234-42. doi: 10.1038/nn1630. Epub 2006 Jan 15. PMID: 16415866.

Liu Y, Xu YF, Zhang L, Huang L, Yu P, Zhu H, Deng W, Qin C. Effective expression of Drebrin in hippocampus improves cognitive function and alleviates lesions of Alzheimer's disease in APP (swe)/PS1 (ΔE9) mice. CNS Neurosci Ther. 2017 Jul;23(7):590-604. doi: 10.1111/cns.12706. Epub 2017 Jun 8. PMID: 28597477; PMCID: PMC6492767.

Ishizuka Y, Shimizu H, Takagi E, Kato M, Yamagata H, Mikuni M, Shirao T. Histone deacetylase mediates the decrease in drebrin cluster density induced by amyloid beta oligomers. Neurochem Int. 2014 Oct;76:114-21. doi: 10.1016/j.neuint.2014.07.005. Epub 2014 Jul 21. PMID: 25058791.