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Event: 2078

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Loss of drebrin

Short name

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Loss of drebrin

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Biological Context

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Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
neuron

Organ term

Organ term
brain

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
postsynaptic actin cytoskeleton organization	drebrin	decreased

Key Event Overview

AOPs Including This Key Event

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AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
IGR binding leads to impairment of learning and memory (via loss of drebrin)	KeyEvent	Shihori Tanabe (send email)	Under development: Not open for comment. Do not cite	Under Development
elavl3, sox10, mbp induced neuronal effects	KeyEvent	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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
Human, rat, mouse	Human, rat, mouse	High	NCBI

Life Stages

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

Life stage	Evidence
During brain development, adulthood and aging	High

Sex Applicability

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

Term	Evidence
Unspecific	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

NMDA-induced excitotoxicity elicits the degradation of drebrin in primary hippocampal and cortical neurons. This process is triggered by calcium influx and mediated by calpains.

Drebrin is an evolutionarily conserved actin-binding protein in dendritic spines. Overexpression of drebrin A in neurons enlarges dendritic spines and decreases spine motility, whereas down-regulation of drebrin A in neurons decreases the density and width of dendritic spines and inhibits synaptic clustering of NMDARs.

Drebrin forms stable actin filaments and plays a pivotal role in dendritic spine morphogenesis (Hayashi and Shirao 1999; Takahashi et al., 2003; Takahashi et al., 2006).

During the initial stage of synaptic plasticity (either LTP or LTD), Ca²⁺ influx through the NMDA receptors arises and it brings out drebrin exodus from dendritic spines (Sekino et al., 2006).

Furthermore, prolonged NMDA-induced excitotoxicity induces calpain-mediated degradation of drebrin in vitro and in vivo.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Loss of drebrin from dendritic spines can be detected by immunocytochemistry, ELISA or or Western blotting (Counts et al., 2006; Ishizuka et al., 2014).

The twenty-one-day primary cultured neurons were prepared using frozen stock of dissociated hippocampal neurons (Koganezawa et al, 2023; Hanamura et al 2019). In brief, cells were cultured in multi well microplates with defined medium.

For immunocytochemistry, the cultured neurons were incubated with chemicals for 1 hour. After fixation, cultured neurons were immunostained with anti-drebrin and anti-MAP2 antibodies. The cluster density of drebrin along the dendrites was automatically quantified using high content analysis instruments (Hanamura et al, 2019, Mitsuoka et al, 2019).

For enzyme-linked immunoassay, after the incubation of chemicals the extracts of neurons were quantified using ELISA kit for drebrin (Higa et al,2024),

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

The results can be applied when developmental neurotoxicity and neurotoxicity in the following way.

1.Drebrin as a biomarker for Neurotoxicity: Drebrin localization in the dendritc spine of matured neuron is hightly sensitive to calcium in flux via NMDA receptors and calpain-mediated degradation. Its critical role in dendritic spine morphology and synaptic function makes it a potential biomarker for assessing neurotoxicity caused by chemical substances.

2.Evaluation of Effects on Synaptic Plasticity: The localization changes and degradation of drebrin can serve as indicators to assess the impact of chemicals on synaptic plasticity (e.g., LTP and LTD).

3.Calcium-dependent Toxicity ;In cases where chemicals induce excitotoxicity through NMDA receptor-mediated calcium influx, drebrin degradation can clarify the specific pathways and extent of neurotoxic damage.

4.Evaluation of Risk mitigation strategied; Chemicals to prevent drebrin degradation can contribute to strategies to rescue the toxicity.

5.Evolutionary Conservation of Drebrin: Drebrin's evolutionary conservation allows for the development of neurotoxicity assessment systems that can be applied across various species, including non-human models, to support broader toxicological evaluations.

Example Scenarios for Application:

Neurotoxicity screening for newly developed chemicals.
Risk assessment of existing chemicals that may increase the likelihood of neurodegenerative diseases.
Providing data for safety standards in industries such as pharmaceuticals, agriculture, and industrial chemicals.

References

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

Koganezawa, N., Roppongi, R.T.,Sekino, Y., Tsutsui, I., Higa, A.,Shirao, T. Easy and Reproducible Low-Density Primary Culture using Frozen Stock of Embryonic Hippocampal Neurons. J. Vis. Exp. (191), e64872, doi:10.3791/64872 (2023).

Mitsuoka T, Hanamura K, Koganezawa N, Kikura-Hanajiri R, Sekino Y, Shirao T. “Assessment of NMDA receptor inhibition of phencyclidine analogues using a high-throughput drebrin immunocytochemical assay” J Pharmacol Toxicol Methods 2019 May 10:106583. doi: 10.1016/j.vascn.2019.106583.

Hanamura K, Koganezawa N, Kamiyama K, Tanaka N, Oka T, Yamamura M, Sekino Y, Shirao T. “High-content imaging analysis for detecting the loss of drebrin clusters along dendrites in cultured hippocampal neurons.” J Pharmacol Toxicol Methods. 2018 Sep - Oct;99:106607. doi: 10.1016/j.vascn.2019.106607.

Chimura T, Launey T, Yoshida N (2015) Calpain-Mediated Degradation of Drebrin by Excitotoxicity In vitro and In vivo. PLoS ONE 10(4): e0125119. doi:10.1371/journal.pone.0125119

Ishizuka, Y. et al. (2014), Histone deacetylase mediates the decrease in drebrin cluster density induced by amyloid beta oligomers. Neurochem Int, 76, 114-121.