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Event: 1983

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Disruption, action potential

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Disruption in action potential generation

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization
Cellular

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). 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 signalling 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. More help
Process Object Action
action potential disrupted

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Inhibition of voltage gate during development is leading to cognitive disorders KeyEvent Arthur Author (send email) Under development: Not open for comment. Do not cite

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. 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
Vertebrates Vertebrates High NCBI
Invertebrates Invertebrates High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
All life stages

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Term Evidence
Male
Female

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. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

An action potential is a fast, transitory and propagating change of the resting membrane potential. Neurons and muscle cells can generate an action potentials. The initial signal comes from other cells connecting to the neuron, and it causes positively charged ions to flow into the cell body. These ions pass through channels that open when a specific neurotransmitter binds to the channel, leading to opening. For example, when acetylcholine is released at the synapse between a nerve and muscle (called the neuromuscular junction) by a presynaptic neuron, it causes postsynaptic Na+ channels to open. Na+ enters the postsynaptic cell and causes the postsynaptic membrane to depolarise. This depolarisation is called an excitatory postsynaptic potential (EPSP) and makes the postsynaptic neuron more likely to fire an action potential. These incoming ions change the membrane potential closer to 0, a process known as depolarisation. When positive ions flow into the negative cell, the cell’s polarity decreases. If it gets positive enough, it can trigger the VGSC found in the axon, then the action potential will be sent.

This process lets positively charged sodium ions flow into the negatively charged axon and depolarise the surrounding axon. Once one channel opens and lets positive ions in, it sets the stage for the channels down the axon to perform the same thing in a domino-like process. This stage is known as depolarisation, the neuron becomes positively charged as the action potential passes through. When the inactivation gates of the sodium channels close, they stop the inward rush of positive ions. At the same time, the potassium channels open. There is much more potassium inside the cell compared with outside, so when these channels open, more potassium exits than enters. The cell therefore loses positively charged ions and returns back toward its resting state. This step is called repolarisation. As the action potential passes through, potassium channels stay open a little bit longer, and continue to let positive ions exit the neuron. This means that the cell temporarily hyperpolarises or gets even more negative than its resting state. As the potassium channels close, the sodium-potassium pump works to re-establish the resting state.

Sodium channel gating is a well regulated process that is critical to normal neuronal function, activation and propagation of the action potential. Shape, speed of conduction and fidelity in propagation of the action potential are essential to the timing, synchrony and efficacy of neuronal communication. Waveform, timing and fidelity of the axonal action potential can be modulated, which leads to changes in presynaptic neurotransmitter release. Action potential normally develops first in the initial segment of the axon. During axonal action potential initiation, the active depolarisation propagates both towards the soma (antidromic) and down the axon (orthodromic). The conduction velocity of the antidromic action potential may have a significant impact on dendritic backpropagation. This in turn will affect spike-timing dependent plasticity i.e. the synaptic plasticity sensitive to the timing of dendritic action potentials relative to incoming synaptic information. The orthodromic velocity will affect the degree of synchrony of arrival of information at different postsynaptic targets of the same axon. In neurons, voltage-gated sodium conductances play an essential role in action potential initiation and propagation. VGSC activate and inactivate within milliseconds. As the cell membrane is depolarised, sodium channels activate, resulting in the influx of sodium ions to further depolarise the membrane. This inward current produces the upstroke of the action potential. Along with the gating of potassium channels, sodium channel inactivation participates in the action potential downstroke. Although variations in many ion channels are likely to participate in the diversity of action potential waveforms observed in neurons, differences in sodium channel subunit composition, localisation and modulation may participate in shaping a neuron’s action potential. Sodium channel subunit composition at the axon initial segment contributes to the firing properties of neurons, particularly the characteristic maximum firing frequency of a particular cell class. Therefore, at nodes of Ranvier the sodium channel subunit composition may contribute to action potential propagation fidelity. Steady-state persistent sodium currents can contribute to excitability and to the shape of an action potential. These sodium channels are active near rest potential (−65 mV) and do not inactivate even with quite strong depolarisation. Therefore, these currents can participate in cellular excitability and in setting action potential threshold (Kress and Mennerick, 2009). Alterations in VGSCs can result in changes in membrane polarisation and propagation of neuronal action potentials. Changes in neuronal excitability in glutamatergic networks are described following treatment to deltamethrin and permethrin on neuronal activity in hippocampal neuronal cultures using patch clamp and microelectrode array (MEA) recordings (Meyer et al., 2008). Cao et al. (2011) demonstrated that VGSC responses of a neuronal network to pyrethroids with an increase of intracellular calcium concentration and these responses are secondary to activation of VGSCs. The effect of pyrethroids on neurotransmitters release and neuronal excitability in glutamatergic networks are described following treatment to deltamethrin and permethrin on neuronal activity in hippocampal neuronal cultures using patch clamp and microelectrode array (MEA) recordings (Meyer et al., 2008). The distinct abilities of pyrethroids to elevate BDNF mRNA expression are consistent with the demonstration of a range of pyrethroid efficacies in the stimulation of calcium influx. In vivo, deltamethrin has been reported to increase BDNF in the cortex and hippocampus (Imamura et al., 2006; Cao et al., 2011), and both deltamethrin and permethrin alter transcription profiles of activity-dependent genes in the cortex including c-fos, Egr1, and Camk1g (Harrill et al., 2008; Cao et al., 2011). Therefore, activity-dependent changes in gene transcription after pyrethroid exposure can occur both in vitro and in vivo (Cao et al., 2011; Pitzer et al., 2019; Zhang et al., 2018).

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. 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).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

The action potential is a cycle of membrane depolarisation, hyperpolarisation and return to the resting value. To measure an action potential, the patch clamp or the intracellular recording (impale a sharp electrode into the cell cytosol) technique are generally used. For either, a glass-made microelectrode is sufficient to measure action potential. The measurement of Na+ ion concentration would not detect single action potentials but a change in bulk ion concentration over a longer time and that might depend mainly on the firing rate of the cells and the activity of Na+/K+-pumps. Patch clamp is the preferred technique for the qualification and quantification of the altered firing rate (Meyer et al., 2008). Neurotransmitter release can be evaluated in vivo using western blotting quantification or using microdialysis and analytical quantification.

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

Action potentials or nerve impulses are rapid and transient electrical activity that is propagated in the membrane of excitable such as neurons and muscle cells. Action potentials allow long-distance signalling in the nervous system. An action potential results from the sequential opening and closing of voltage-gated cation channels. First, opening of Na+ channels permits influx of Na+ ions for about 1 ms, causing a sudden large depolarisation of a segment of the membrane. The channel then closes and becomes unable to open (refractory) for several milliseconds, preventing further Na+ flow. Opening of K+ channels as the action potential reaches its peak permits efflux of K+ ions, which initially hyperpolarises the membrane. As these channels close, the membrane returns to its resting potential. The same basic mechanism is used by all neurons. Myelination produced by oligodendrocytes increases the velocity of impulse conduction (Lodish et al., 2000, ‘The Action Potential and Conduction of Electric Impulses’ in Molecular Cell Biology Section 21.2, New York )

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

Cao Z, Shafer TJ and Murray TF, 2011. Mechanisms of pyrethroid insecticide-induced stimulation of calcium influx in neocortical neurons, Journal of Pharmacology and Experimental Therapeutics, 336(1), 197–205. doi: https://doi.org/10.1124/jpet.110.171850

Harrill JA, Li Z, Wright FA, Radio NM, Mundy WR, Tornero-Velez R and Crofton KM, 2008. Transcriptional response of rat frontal cortex following acute in vivo exposure to the pyrethroid insecticides permethrin and deltamethrin. BMC Genomics, 9(1), 546. https://doi.org/10.1186/1471-2164-9-546

Imamura L, Yasuda M, Kuramitsu K, Hara D, Tabuchi A and Tsuda M, 2006. Deltamethrin, a pyrethroid insecticide, is a potent inducer for the activity-dependent gene expression of brain-derived neurotrophic factor in neurons. Journal of Pharmacology and Experimental Therapeutics, 316(1), 136–143. doi: 10.1124/jpet.105.092478

Kress GJ and Mennerick S, 2009. Action potential initiation and propagation: upstream influences on neurotransmission. Neuroscience, 158(1), 211–222.

Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D and Darnell J. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000. Section 21.2, The Action Potential and Conduction of Electric Impulses. Available from: https://www.ncbi.nlm.nih.gov/books/NBK21668/

Meyer DA, Carter JM, Johnstone AF and Shafer TJ, 2008. Pyrethroid modulation of spontaneous neuronal excitability and neurotransmission in hippocampal neurons in culture. Neurotoxicology, 29(2), 213– 225. doi: 10.1016/j.neuro.2007.11.005.

Pitzer EM, Sugimoto C, Gudelsky GA, Huff Adams CL, Williams MT and Vorhees CV, 2019. Deltamethrin exposure daily from postnatal day 3–20 in Sprague-Dawley rats causes long-term cognitive and behavioral deficits. Toxicological Sciences, 169(2), 511–523. https://doi.org/10.1093/toxsci/kfz067 Zhang C, Xu Q, Xiao X, Li W, Kang Q,

Zhang X, … and Li Y, 2018. Prenatal deltamethrin exposureinduced cognitive impairment in offspring is ameliorated by memantine through NMDAR/BDNF signaling in hippocampus, Frontiers in Neuroscience, 12, 615. https://doi.org/10.3389/fnins.2018.00615