Aop: 475

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Binding of chemicals to ionotropic glutamate receptors leads to impairment of learning and memory via loss of drebrin from dendritic spines of neurons

Short name
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IGR binding leads to impairment of learning and memory (via loss of drebrin)

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

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Yuko Sekino1, Shihori Tanabe2, Tomoaki Shirao3

1 the University of Tokyo, Japan

2 National Institute of Health Sciences, Japan

3 Gunma University, Japan

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Shihori Tanabe   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Shihori Tanabe
  • Yuko Sekino

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite
This AOP was last modified on January 16, 2023 03:47

Revision dates for related pages

Page Revision Date/Time
Binding of agonist, Ionotropic glutamate receptors September 16, 2017 10:15
Overactivation, NMDARs January 04, 2023 18:39
Loss of drebrin December 11, 2022 21:04
Synaptic dysfunction January 04, 2023 18:47
Impairment, Learning and memory July 12, 2022 09:02
Increased, Intracellular Calcium overload June 26, 2020 04:45
Binding of agonist, Ionotropic glutamate receptors leads to Overactivation, NMDARs November 29, 2016 20:44
Overactivation, NMDARs leads to Loss of drebrin December 11, 2022 21:08
Overactivation, NMDARs leads to Increased, Intracellular Calcium overload November 29, 2016 20:08
Loss of drebrin leads to Dysfunctional synapses December 11, 2022 21:08
Dysfunctional synapses leads to Impairment, Learning and memory December 11, 2022 21:08

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

Neurotoxicity risk assessment is an important issue for regulatory agencies. Currently, chemicals with potential risks are determined by time-consuming and costly animal testing. Therefore, in vitro testing methods are needed to rapidly evaluate thousands of chemicals for which no safety data on neurotoxicity exist. In recent years, chemicals that induce learning and memory impairment are thought to increase the risk of neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Therefore, such risk assessment is necessary for human safety. The existing AOP No. 6 in OECD Series on AOPs (AOP48 in the AOP-Wiki) defines a molecular initiating event (MIE) as “Binding of agonists to ionotropic glutamate receptors”, causing neuronal cell death linked to impairment of learning and memory through receptor hyperactivation(1).

Recent studies have shown that synaptic dysfunction precedes neuronal death in the early stages of dementia accompanied with the neurodegenerative diseases. Synaptic dysfunction is presumed as a decrease in the number of dendritic spines in neurons of the cerebral cortex and hippocampus, which are essential for learning and memory(2). Therefore, the risk for impairment of learning and memory can be assessed by the synaptic dysfunction, namely decreased number of dendritic spines(3).

Dendritic spines are small actin-rich projections protruding from the dendrites of neurons that form excitatory synapses in the cortex and hippocampus(4). Drebrin is an actin-binding protein that localizes to dendritic spines and is said to play a specific role in their formation(5). Drebrin is known to decrease in Alzheimer's disease with a high correlation to symptom stage(6,7). In low-density cultures of hippocampal neurons, the number of dendritic spines can be counted as the number of drebrin clusters with immunostaining.

We have developed an experimental protocol for low-density neuronal culture in 96-well plates and an algorithm that automatically counts the number of drebrin clusters by high-content imaging analysis(8). These protocols have been shown to be useful for screening chemicals that bind to the NMDA receptor. In fact, we have examined the toxicity of phencyclidine (PCP) and PCP-analogues and published results in a paper(9). We have developed not only the immunocytochemical protocol for in vitro assay using neuronal culture but also enzyme-linked immunosorbent assay (ELISA) kits to evaluate drebrin protein levels. Thus, decreased number of dendritic spines induced by chemicals can be assessed quantitatively as a loss of drebrin immunocytochemically and biochemically.

Here, we propose a new AOP with the same MIE as AOP No. 6, in which loss of drebrin as KE leads to impairment of learning and memory. Studies of genetically engineered mice have shown that drebrin deficiency is directly related to synaptic dysfunction and leads to the impairment of learning and memory, even in the absence of neuronal cell death(10,11,12). This is the most important distinction between the proposed AOP and the existing AOP. Measurement of drebrin expression levels in neurons with immunocytochemistry and/or ELISA is easy and high-reproducible. The new KE, loss of drebrin, will promote accumulation of data of chemicals for neurotoxicity. The proposed AOP is expected to contribute to the development of many in vitro test for neurotoxicity and to establish in silico prediction to evaluate safety of many substances for human and environments.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

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Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 875 Binding of agonist, Ionotropic glutamate receptors Binding of agonist, Ionotropic glutamate receptors
KE 388 Overactivation, NMDARs Overactivation, NMDARs
KE 389 Increased, Intracellular Calcium overload Increased, Intracellular Calcium overload
KE 2078 Loss of drebrin Loss of drebrin
KE 1944 Synaptic dysfunction Dysfunctional synapses
AO 341 Impairment, Learning and memory Impairment, Learning and memory

Relationships Between Two Key Events (Including MIEs and AOs)

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Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

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Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Taxonomic Applicability

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Sex Applicability

The sex for which the AOP is known to be applicable. More help

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

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Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help
Modulating Factor (MF) Influence or Outcome KER(s) involved
     

Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help
  1. Adverse Outcome Pathway on binding of agonists to ionotropic glutamate receptors in adult brain leading to excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment, Sachana M, et al. OECD Series on Adverse Outcome Pathways (2016) No. 6, OECD Publishing, Paris, doi: 10.1787/5jlr8vqgm630-en.
  2. Synapse pathology in Alzheimer’s disease, Griffiths J, Grant GN. Seminars in Cell and Developmental Biology (2022) doi: 10.1016/j.semcdb.2022.05.028. (review)
  3. Dopamine Restores Limbic Memory Loss, Dendritic Spine Structure, and NMDAR-Dependent LTD in the Nucleus Accumbens of Alcohol-Withdrawn Rats Cannizzaro C, et al. J Neurosci. (2019) Jan 30;39(5):929-943. doi: 10.1523/JNEUROSCI.1377-18.2018.
  4. Actin in dendritic spines: connecting dynamics to function, Hotulainen P, Hoogenraad C. J Cell Biol (2010) 17;189(4):619-29. doi: 10.1083/jcb. 201003008. (review)
  5. Role of actin cytoskeleton in dendritic spine morphogenesis. Sekino Y, et al. Neurochem Int. (2007) 51(2-4):92-104. doi: 10.1016/j.neuint.2007.04.029. (review)
  6. Drebrin, a dendritic spine protein, is manifold decreased in brains of patients with Alzheimer’s disease and Down syndrome Shim KS, Lubec G. Neurosci Lett. 2002 May 24;324(3):209-12. doi: 10.1016/s0304-3940(02)00210-0.
  7. Differential expression of synaptic proteins in the frontal and temporal cortex of elderly subjects with mild cognitive impairment, Counts SE, et al.  J Neuropathol Exp Neurol. 2006 Jun;65(6):592-601. doi: 10.1097/00005072-200606000-00007.
  8. High-content imaging analysis for detecting the loss of drebrin clusters along dendrites in cultured hippocampal neurons Hanamura K, et al. J Pharmacol Toxicol Methods. (2019) 99:106607. doi: 10.1016/j.vascn.2019.106607.
  9. Assessment of NMDA receptor inhibition of phencyclidine analogues using a high-throughput drebrin immunocytochemical assay Mitsuoka T, et al. J Pharmacol Toxicol Methods. (2019) 99:106583. doi: 10.1016/j.vascn.2019
  10. Genetic disruption of the alternative splicing of drebrin gene impairs context-dependent fear learning in adulthood, Kojima N, et al. Neuroscience. (2010) 165(1):138-50. Doi: 10.1016/j.neuroscience.2009.10.016.
  11. Drebrin A regulates hippocampal LTP and hippocampus-dependent fear learning in adult mice, Kojima N, et al. Neuroscience. (2016) Jun 2;324:218-26. doi: 10.1016/j.neuroscience.2016.03.015.
  12. Effective expression of Drebrin in hippocampus improves cognitive function and alleviates lesions of Alzheimer’s disease in APP (swe)/PS1 (ΔE9) mice, Liu Y, et al. CNS Neurosci Ther. (2017) Jul;23(7):590-604. doi: 10.1111/cns.12706.