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Relationship: 634


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

Decreased, Neuronal network function in adult brain leads to Impairment, Learning and memory

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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 agonists to ionotropic glutamate receptors in adult brain causes excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment. adjacent Moderate Low Anna Price (send email) Open for citation & comment WPHA/WNT Endorsed

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 Homo sapiens High NCBI
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI

Sex Applicability

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

Life Stage Applicability

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

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

It is well established in the existing literature that NMDA receptor–dependent synaptic potentiation (LTP) and depression (LTD) are two forms of activity directly linked to long-term changes in synaptic efficacy and plasticity, the fundamental processes underlying learning and memory. The best characterized form of LTP occurs in the CA3-CA1 region of the hippocampus, in which LTP is initiated by transient activation of NMDARs that leads to a persistent increase in synaptic transmission through AMPA receptors (Benke et al., 1998) that can be achieved either through increasing the number of AMPA receptors at the post-synaptic surface or by increasing the single channel conductance of the receptors expressed. It has been shown that LTP in the CA1 region of the hippocampus could be accounted for by these two mechanisms (Benke et al 1998). The degree of activity of NMDARs is determined in part by extracellular Mg(2+) and by the co-agonists for this receptor, glycine and D-serine. During strong stimulation, a relief of the voltage-dependent block of NMDARs by Mg(2+) provides a positive feedback for NMDAR Ca(2+) influx into postsynaptic CA1 spines. The induction of LTP at CA3-CA1 synapses requires further signal amplification of NMDAR activity. Src family kinases (SFKs) play a "core" role in the induction of LTP by enhancing the function and expression of NMDARs. At CA3-CA1 synapses, NMDARs are largely composed of NR1 (NMDA receptor subunit 1)-NR2A or NR1-NR2B containing subunits. Recent, but controversial, evidence has correlated NR1-NR2A receptors with the induction of LTP and NR1-NR2B receptors with LTD. However, LTP can be induced by activation of either subtype of NMDAR and the ratio of NR2A:NR2B receptors has been proposed as an alternative determinant of the direction of synaptic plasticity. Many transmitters and signal pathways can modify NMDAR function and expression and, for a given stimulus strength, they can potentially lead to a change in the balance between LTP and LTD (MacDonald et al., 2006).

Mammalian learning and memory is one of the outcomes of the functional expression of neurons connected into neural networks. Neuronal damage or cell death induced by chemical compounds disrupts integration and transmission of information through neural networks thereby setting the stage for subsequent impairment of learning and memory. Exposure to chemicals that will increase the risk of functional neuronal network damage lead to learning and memory impairment.

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

Evidence Supporting this KER

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

Long-term potentiation (LTP) is a long-lasting increase in synaptic efficacy after high-frequency stimulation of afferent fibers, and its discovery potentiated the idea that individual synapses possess the properties expected for learning and memory (reviewed in Lynch et al., 2014). Moreover, LTP is intimately related to the theta rhythm, an oscillation long-associated with learning. Learning-induced enhancement in neuronal excitability, a measurement of neural network function, has also been shown in hippocampal neurons following classical conditioning in several experimental approaches (reviewed in Saar and Barkai, 2003). On the other hand, memory requires the increase in magnitude of EPSCs to be developed quickly and to be persistent for a at least a few weeks without disturbing already potentiated contacts. Once again, a substantial body of evidence have demonstrated that tight connection between LTP and diverse instances of memory exist (reviewed in Lynch et al., 2014).

The recent studies suggest that NMDA receptor-dependent long-term depression of both LTD and LTP is usually accompanied by morphological changes in spines. LTD is characterized by long lasting dendritic spine shrinkage and reduced F-actin polymerization, in addition to reduced numbers of synaptic AMPA receptors. Moreover, the actin binding protein cofilin has been implicated in mediating such synaptic structural plasticity (Chen et al., 2007). If sustained, such LTD-changes in hippocampus or cortex, triggered by NMDARs overactivation could lead to synaptic dysfunction, contributing to learning and memory damage (Calabrese et al., 2014).

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

One of the most difficult issues for neuroscientists is to link neuronal network function to cognition, including learning and memory. It is still unclear exactly what modifications in neuronal circuits need to happen in order to alter motor behaviour as it is recorded in a learning and memory test (Mayford et al., 2012), meaning that there is no clear understanding about how these two KEs are connected.

It is unclear whether GLF affects only glutamatergic systems since other potential mechanisms underlying GLF neurotoxicity have not been widely investigated. Based on the existing data it is understood that exposure to GLF or NAcGLF could disrupt the neuronal network function through disruption of glutamatergic neurotransmission but further work is required to clarify molecular mechanisms that cause impairment of memory.

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
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

Administration of DomA (9.0 mg DomA kg(-1) bw, i.p.) to Sparus aurata (seabream) caused neurological disturbances such as swimming in a circle, in a spiral, or upside down, that were reversed 24 hours after exposure (Nogueira et al., 2010). In rainbow trout (Oncorhynchus mykiss), DomA (0.75 mg/kg bw) administration caused increased aggressive behaviour 30 min after exposure compared to controls (Bakke et al., 2010).


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

Bakke MJ, Hustoft HK, Horsberg TE., Subclinical effects of saxitoxin and domoic acid on aggressive behaviour and monoaminergic turnover in rainbow trout (Oncorhynchus mykiss). Aquat Toxicol., 2010, 99: 1-9.

Baron AW, Rushton SP, Rens N, Morris CM, Blain PG, Judge SJ., Sex differences in effects of low level domoic acid exposure. Neurotoxicology, 2013, 34: 1-8.

Benke TA1, Lüthi A, Isaac JT, Collingridge GL., Modulation of AMPA receptor unitary conductance by synaptic activity. Nature, 1998, 25: 793-7.

Calabrese B, Saffin JM, Halpain S. Activity-dependent dendritic spine shrinkage and growth involve downregulation of cofilin via distinct mechanisms. PLoS One, 2014, 16;9(4):e94787.

Calas AG, Richard O, Même S, Beloeil JC, Doan BT, Gefflaut T, Même W, Crusio WE, Pichon J, Montécot C. Chronic exposure to glufosinate-ammonium induces spatial memory impairments, hippocampal MRI modifications and glutamine synthetase activation in mice. Neurotoxicology. 2008, 29(4): 740-7

Chen LY, Rex CS, Casale MS, Gall CM, Lynch G., Changes in synaptic morphology accompany actin signaling during LTP. J Neurosci., 2007, 27: 5363–5372.

Clayton EC, Peng YG, Means LW, Ramsdell JS. Working memory deficits induced by single but not repeated exposures to domoic acid. Toxicon. 1999, 37: 1025-1039.

D'Hooge R, De Deyn PP., Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev., 2001, 36: 60-90.

Fuquay JM, Muha N, Pennington PL, Ramsdell JS., Domoic acid induced status epilepticus promotes aggressive behavior in rats. Physiol Behav., 2012, 105: 315-320.

Grant KS, Burbacher TM, Faustman EM, Gratttan L., Domoic acid: neurobehavioral consequences of exposure to a prevalent marine biotoxin. Neurotoxicol Teratol., 2010, 32: 132-141.

Grunwald T, Beck H, Lehnertz K, Blümcke I, Pezer N, Kurthen M, Fernández G, Van Roost D, Heinze HJ, Kutas M, Elger CE.. Evidence relating human verbal memory to hippocampal N-methyl-D-aspartate receptors. Proc Natl Acad Sci U S A., 1999, 96: 12085-12089.

Hiolski EM, Kendrick PS, Frame ER, Myers MS, Bammler TK, Beyer RP, Farin FM, Wilkerson HW, Smith DR, Marcinek DJ, Lefebvre KA., Chronic low-level domoic acid exposure alters gene transcription and impairs mitochondrial function in the CNS. Aquat Toxicol., 2014, 155: 151-9.

Koyama K, Andou Y, Saruki K, Matsuo H., Delayed and severe toxicities of a herbicide containing glufosinate and a surfactant. Vet Hum Toxicol., 1994, 36: 17–8.

Kuhlmann AC, Guilarte TR., The peripheral benzodiazepine receptor is a sensitive indicator of domoic acid neurotoxicity. Brain Res., 1997, 751: 281-288.

Lantz SR, Mack CM, Wallace K, Key EF, Shafer TJ, Casida JE., Glufosinate binds to N-methyl-D-aspartate receptors and increases neuronal network activity in vitro. Neurotoxicology, 2014, 45:38-47.

Lu J, Wu DM, Zheng YL, Hu B, Cheng W, Zhang ZF., Purple sweet potato color attenuates domoic acid-induced cognitive deficits by promoting estrogen receptor-α-mediated mitochondrial biogenesis signaling in mice. Free Radic Biol Med., 2012, 52: 646-59.

Lynch G, Cox CD, Gall CM., Pharmacological enhancement of memory or cognition in normal subjects. Front Syst Neurosci., 2014, 8: 90-103.

MacDonald JF1, Jackson MF., Beazely MAHippocampal long-term synaptic plasticity and signal amplification of NMDA receptors. Crit Rev Neurobiol., 2006, 18: 71-84.

Mao Y-C, Hung D-Z, Wu M-L, Tsai W-J, Wang L-M, Ger J, et al. Acute human glufosinatecontaining herbicide poisoning. Clin Toxicol., 2012, 5: 1–7.

Mao Y-C, Wang J-D, Hung D-Z, Deng J-F, Yang C-C., Hyperammonemia following glufosinate-containing herbicide poisoning: a potential marker of severe neurotoxicity. Clin Toxicol (Phila), 2011a, 49: 48–52.

Mao Y-C, Yang C-C. Response to ‘‘Hyperammonemia following glufosinate-containing herbicide poisoning: A potential marker of severe neurotoxicity’’ by Yan-Chido Mao et al., Clin Toxicol (Phila) 2011b; 49: 48–52. Clin Toxicol 2011;49(July (6)): 513.

Mayford M, Siegelbaum SA, Kandel ER., Synapses and memory storage. Cold Spring Harb Perspect Biol., 2012:4(6). pii: a005751.

Meme S, Calas A-G, Monte´ cot C, Richard O, Gautier H, Gefflaut T, et al., MRI characteri- zation of structural mouse brain changes in response to chronic exposure to the glufosinate ammonium herbicide. Toxicol Sci 2009, 111: 321–30.

Matsumura N, Takeuchi C, Hishikawa K, Fujii T, Nakaki T., Glufosinate ammonium induces convulsion through N-methyl-D-aspartate receptors in mice. Neurosci Lett., 2001, 304(1-2): 123-5.

Morris RG, Anderson E, Lynch GS, Baudry M.,Selective impairment of learning and blockade of long-term potentiation by an N-methyl-Daspartate receptor antagonist, AP5. Nature, 1986, 319: 774-776.

Muha N, Ramsdell JS., Domoic acid induced seizures progress to a chronic state of epilepsy in rats. Toxicon., 2011, 57: 168-171.

Nakajima S, Potvin JL., Neural and behavioural effects of domoic acid, an amnesic shellfish toxin, in the rat. Can J Psychol., 1992, 46: 569-581.

Nogueira I, Lobo-da-Cunha A, Afonso A, Rivera S, Azevedo J, Monteiro R, Cervantes R, Gago-Martinez A, Vasconcelos V., Toxic effects of domoic acid in the seabream Sparus aurata. Mar Drugs, 2010, 8: 2721-232.

Ohtake T, Yasuda H, Takahashi H, Goto T, Suzuki K, Yonemura K, et al., Decreased plasma and cerebrospinal fluid glutamine concentrations in a patient with bialaphos poisoning. Hum Exp Toxicol., 2001, 20: 429–34.

Park JS1, Kwak SJ, Gil HW, Kim SY, Hong SY., Glufosinate herbicide intoxication causing unconsciousness, convulsion, and 6th cranial nerve palsy. J Korean Med Sci., 2013, 28:1687-9.

Park HY, Lee PH, Shin DH, Kim GW., Anterograde amnesia with hippocampal lesions following glufosinate intoxication. Neurology, 2006, 67:914–5.

Petrie BF, Pinsky C, Standish NM, Bose R, Glavin GB., Parenteral domoic acid impairs spatial learning in mice. Pharmacol Biochem Beh., 1992, 41: 211-214.

Pulido OM., Domoic acid toxicologic pathway: a review. Mar Drugs, 2008, 6:180-219.

Saar D, Barkai E. (2003) Long-term modifications in intrinsic neuronal properties and rule learning in rats. Eur J Neurosci. 17: 2727-2734.

Sobotka TJ, Brown R, Quander DY, Jackson R, Smith M, Long SA, Barton CN, Rountree RL, Hall S, Eilers P, Johannessen JN, Scallet AC., Domoic acid: neurobehavioral and neurohistological effects of low-dose exposure in adult rats. Neurotoxicol Teratol., 1996, 18: 659-670.

Tryphonas L, Truelove J, Nera E, Iverson F., Acute neurotoxicity of domoic acid in the rat. Toxicol Pathol., 1990, 18: 1-9.

Watanabe T, Sano T., Neurological effects of glufosinate poisoning with a brief review. Hum Exp Toxicol., 1998, 17(1): 35-9.

Wu DM, Lu J, Zheng YL, Zhang YQ, Hu B, Cheng W, Zhang ZF, Li MQ., Small interfering RNA-mediated knockdown of protein kinase C zeta attenuates domoic acid-induced cognitive deficits in mice. Toxicol Sci., 2012, 128: 209-222.

Wu DM, Lu J, Zhang YQ, Zheng YL, Hu B, Cheng W, Zhang ZF, Li MQ., Ursolic acid improves domoic acid-induced cognitive deficits in mice. Toxicol Appl Pharmacol., 2013, 271: 27-36.

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