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Event: 382

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

Aberrant, Dendritic morphology

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
Aberrant, Dendritic morphology

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
Cell term
neuron

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
dendrite morphogenesis dendrite abnormal

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
Binding of antagonist to NMDARs impairs cognition KeyEvent Anna Price (send email) Open for citation & comment WPHA/WNT Endorsed

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
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
mouse Mus musculus High NCBI
chicken Gallus gallus High NCBI
fruit fly Drosophila melanogaster 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

Sex Applicability

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

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

Biological state: After becoming post-mitotic and during the differentiation process, neuronal cells undergo lengthening, branching, dendrite and dendritic spine formation (Scott and Luo, 2001). In human, dendrites appear as early as 13.5 weeks gestation in the subplate neurons while arborization begins only after 26 weeks (Mrzljak et al., 1988 and Mrzljak et al., 1990). In rodents, during the first postnatal week, both pyramidal and nonpyramidal neurons go through extensive and fast dendrite growth, branching, and elaboration. Dendrite arbor's capacity and complexity continue to increase in the second and third postnatal week, however, much slower. During the same developmental window, dendritic spines begin to appear as a group. The first spines look like filopodia (Dailey and Smith, 1996; Fiala et al., 1998). Filopodia can grow and retract within seconds to minutes, permitting them to explore and identify appropriate presynaptic targets (Dailey and Smith, 1996). As dendrite spines mature, these long and thin structures change and the spines shorten and acquire a bulbous ending or ‘head’ (Dailey and Smith, 1996). At this final stage of dendrite growth, a neuron possesses a dynamic dendrite tree, which has a greater potential for connectivity and synapse creation because of dendritic spine formation.

Biological compartments: Dendritic morphology determines many aspects of neuronal function, including action potential propagation and information processing. Postsynaptic density-95 (PSD-95), a protein involved in dendritic spine maturation and clustering of synaptic signalling proteins, plays a critical role in regulating dendrite outgrowth and branching, independent of its synaptic functions. In immature neurons, over-expression of PSD-95 decreases the proportion of primary dendrites that undergo additional branching, resulting in a marked reduction of secondary dendrite number. Conversely, knocking down PSD-95 protein in immature neurons increases secondary dendrite number. Binding of cypin to PSD-95 (that regulates PSD-95 location) correlates with formation of stable dendrite branches. Finally, overexpression of PSD-95 in COS-7 cells disrupts microtubule organization, indicating that PSD-95 may modulate microtubules to regulate dendritic branching. Proteins primarily involved in synaptic functions can also play developmental roles in shaping how a neuron patterns its dendrite branches (Kornau et al., 1995). New spines containing PSDs are formed by conversion of dynamic filopodia-like spine precursors in which PSDs appeared de novo, or by direct extension of spines or spine precursors carrying preformed PSDs from the shaft. PSDs are therefore highly dynamic structures that can undergo rapid structural alteration within dendrite shafts, spines and spine precursors, permitting rapid formation and re-modelling of synaptic connections in developing CNS tissues.

Dendritic spines are important sites of excitatory synaptic transmission and changes in the strength of these synapses are likely to underlie important higher brain functions such as learning and memory. Spines form biochemical compartments for isolating reactions that occur at one synapse from those at other synapses thereby providing a possible way to ensure the specificity of connections between neurons in the brain.

The stages of dendrite development have been clearly described in neurons located in the developing rodent cortex and hippocampus (Dailey and Smith, 1996; Fiala et al., 1998; Redmond, 2008) and human prefrontal cortex (Mrzljak et al., 1988; Mrzljak et al., 1990).

General role in biology: Functionally, dendrites serve as post-synaptic part of a synapse, playing a critical role in the processing of information transmitted through synapses. They receive the majority of synaptic inputs comparing to the soma or the axon. Consequently, it is not surprising that postsynaptic activity is closely related to the properties of the dendritic arbor itself, implying that the dendrites strongly influence and control synaptic transmission and plasticity (Sjöström et al., 2008).

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). ?

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

Elaboration of dendritic processes is measured from electron and fluorescent micrographs. These processes are identified primarily by the presence of microtubule associated protein 2 (MAP-2) and the absence of components characteristic of axons and glia (e.g. small vesicles, myelin, glial filaments).These measurements can also be carried out by automated imaging systems in cells prepared for immunohistochemistry with specific antibodies that recognise MAP-2 (Harrill and Mundy, 2011).

Two-photon time-lapse images can be used to visualise dendrites in GFP-transfected neurons, whereas Golgi Stain Kit is used to measure both dendrites and dendritic spines. A combination of Golgi-Cox and immunofluorescence using confocal microscopy has also been suggested for the visualisation of dendrites in brain slices derived either from rodents or non-human primates (Levine et al., 2013).

The morphological analysis of neurons, include the use of fluorescent markers, such as DiI (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate) that permits not only the visualisation of detailed dendritic arborizations and spines in cell culture and tissue sections but also permits the quantitative analysis of dendritic spines (Cheng et al., 2014).

Fluorescent labelling for MARCM (mosaic analysis with a repressible cell marker) system can also be used but only in case of transparent larval body wall found in Drosophila.

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

Drosophila is one of the best-studied models that allow examining how diverse dendrite morphologies are formed during development (Grueber et al., 2002). The chick embryo (Gallus domesticus) is another important model in vertebrate developmental neurobiology where the dendritic arbor development has been extensively studied (Rubel and Fritzsch, 2002). Different methods have also been used to study dendritic arborization and spine formation in brain sections and cell cultures derived by rodents (Stansfield et al., 2012) and primates (Khazipov et al., 2001).

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

Cheng C, Trzcinski O, Doering LC. (2014) Fluorescent labeling of dendritic spines in cell cultures with the carbocyanine dye "DiI". Front Neuroanat. 8: 30.

Dailey ME, Smith SJ. (1996) The dynamics of dendritic structure in developing hippocampal slices. J Neurosci. 16: 2983-2994.

Fiala JC, Feinberg M, Popov V, Harris KM. (1998) Synaptogenesis via dendritic filopodia in developing hippocampal area CA1. J Neurosci. 18: 8900-8911.

Grueber WB, Jan LY, Jan YN. (2002) Tiling of the Drosophila epidermis by multidendritic sensory neurons. Development 129: 2867-2878.

Harrill JA, Mundy WR. (2011) Quantitative assessment of neurite outgrowth in PC12 cells. Methods Mol Biol. 758: 331-348.

Khazipov R, Esclapez M, Caillard O, Bernard C, Khalilov I, Tyzio R, Hirsch J, Dzhala V, Berger B, Ben-Ari Y. (2001) Early development of neuronal activity in the primate hippocampus in utero. J Neurosci. 21: 977097-81.

Kornau HC, LT Schenker, MB Kennedy, PH Seeburg. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 22 September 1995: Vol. 269 no. 5231 pp. 1737-1740

Levine ND, Rademacher DJ, Collier TJ, O'Malley JA, Kells AP, San Sebastian W, Bankiewicz KS, Steece-Collier K. (2013) Advances in thin tissue Golgi-Cox impregnation: fast, reliable methods for multi-assay analyses in rodent and non-human primate brain. J Neurosci Methods 213: 214-227.

Mrzljak L, Uylings HB, Kostovic I, Van Eden CG. (1988). Prenatal development of neurons in the human prefrontal cortex: I. A qualitative Golgi study. J Compar Neurol. 271: 355-386.

Mrzljak L, Uylings HB, Van Eden CG, Judas M. (1990). Neuronal development in human prefrontal cortex in prenatal and postnatal stages. Prog Brain Res. 85: 185-222.

Redmond L. (2008) Translating neuronal activity into dendrite elaboration: signaling to the nucleus. Neurosignals 16: 194-208.

Rubel EW, Fritzsch B. (2002) Auditory system development: primary auditory neurons and their targets. Annu Rev Neurosci. 25: 51-101.

Scott EK, Luo L: (2001) How do dendrites take their shape? Nat Neurosci. 4: 359-365.

Sjöström PJ, Rancz EA, Roth A, Häusser M. (2008) Dendritic excitability and synaptic plasticity. Physiol Rev. 88: 769-840.

Stansfield KH, Pilsner JR, Lu Q, Wright RO, Guilarte TR. (2012) Dysregulation of BDNF-TrkB signaling in developing hippocampal neurons by Pb(2+): implications for an environmental basis of neurodevelopmental disorders. Toxicol Sci. 127: 277-295.