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Relationship: 3243

Title

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

neurotrasmission in development leads to Hippocampal anatomy, Altered

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 to voltage gate sodium channels during development leads to cognitive impairment adjacent Iris Mangas (send email) Under development: Not open for comment. Do not cite Under Review

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
Vertebrates Vertebrates High NCBI
Invertebrates Invertebrates High NCBI
rat Rattus norvegicus Moderate NCBI
mouse Mus musculus Moderate NCBI
human Homo sapiens Not Specified NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male High
Female High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
During brain development High
Development High

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 that neurons extend and retract their pre and postsynaptic processes dependent on the level of neuronal activation (Andrae et a., 2014). These growth processes determine the basic shape of a neuron and its regions of afferent and efferent connections, processes critical during brain development. Neural systems encode information structurally via the wiring between neurons and this wiring is modulated by the electrical activity in both the developing and adult nervous systems. Establishment of synaptic connectivity begins as a diffuse process that is refined in an activity-dependent manner during development (Pan and Monje, 2020). Disruption of the formation of precise neural circuits during the prenatal and perinatal stages of brain development may underlie neurodevelopmental disorders.

At birth, an infant’s brain contains more neurons than present in the adult. As the child grows, experiences strengthen circuits that prove more relevant and weaken others. This process of overgrowth followed by selective activity-dependent elimination is key to forming an adaptive brain, with waves of neuronal cell death and dramatic reduction in connecting axonal fibers occurring during development (Anosike et al., 2023). The process whereby a subset of synapses is removed, while others are maintained is called synaptic pruning. It is a fundamental property of the mammalian CNS, it occurs in response to changes in neural activity, and it is most prominent in the developing nervous system (Faust et al., 2021). The lack of activity at most synapses on a neuron can lead to the eventual death of that cell. As such, interference with electrical signaling during development can certainly influence connectivity of the developing brain.

The activity-dependent processes alter both the structure of the axonal bouton of presynaptic and the dendritic spine of the postsynaptic neuron. Spines can change in shape, volume, density, and location. Overall activity levels can increase or decrease spine number, dendritic branches can be expanded or eliminated, axons removed or redirected to novel destinations based on the level of activity with the synaptic network. Denervation inducing a total lack of neuronal activity can induce axonal growth and expansion to other areas.

Spontaneous neurotransmitter release plays an important role in shaping neuronal morphology as well as modulating the properties of newly forming synaptic connections in the brain (Andreae and Burrone, 2018). Excessive or insufficient neurotransmission during critical windows of development can affect the complexity of the connectivity within pre and post-synaptic neurons, leading to altered synaptic density and connectivity. The delicate balance between excitatory (glutamatergic) and inhibitory (GABAergic) neurotransmission shapes brain circuitry, and when perturbed, it can lead to abnormal network activity (Cherubini et al., 2021). This has been widely studied in the hippocampus.

There are two types of structural remodelling, one occurs fast (minutes to hours), the other on a more protracted (hours, days, weeks) timescale. Activity-dependent remodelling can occur at ultrastructural, network, and regional levels, and in the developing nervous system as well as the mature brain (see review by Fauth and Tetzlaff, 2016). Changes in neuronal architecture driven by activity are known to occur in all brain areas studied to date including the hippocampus.

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

This KER was originally created as part of an evidence-based AOP informed IATA for deltamethrin for developmental neurotoxicity hazard characterization. The IATA case study was developed to support human health risk assessment of deltamethrin pesticide active substance and as a proof-of-concept on the applicability of the data provided in the Developmental Neurotoxicity In vitro Battery to apply mechanistic understanding of toxicity pathways for regulatory decision making (DNT IVB OECD., 2023). Using systematic searches and expert knowledge the initial KER was updated by an EFSA Working Group.

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

The biological plausibility of altered neurotransmission during the development and further impairment of hippocampal anatomy is strong. Extensive evidence supports the notion that disruption of neurotransmission during development can induce micro-structural morphological changes in the hippocampus. This can occur because of various factors such as genetic mutations, brain damage, environmental toxins, and stress during vulnerable periods of brain development.

Impaired synaptic transmission may occur at pre- or postsynaptic level and involves disruption of the normal functioning of neurotransmitters, their receptors, or scaffolding proteins. The strength of the synaptic transmission can be modulated by the amount of neurotransmitter released, the number of receptors on the postsynaptic cell, and their sensitivity to the neurotransmitter due to alterations in the number and conductance of postsynaptic receptors (Graziane and Dong, 2022; Hestrin, 2015). In case of presynaptic dysfunction, either too much or too little neurotransmitter may be released into the synaptic cleft, whereas in postsynaptic dysfunction, the postsynaptic neuron may not respond adequately to that neurotransmitter. In both cases, the altered synaptic transmission may have pre- or postsynaptic morphological consequences, including e.g. number of docked vesicles at the nerve terminal, or the number, density and morphology of dendrite spines. These changes may affect the structure and function of neural circuits and may underlie behavioral deficits (Bonnycastle et al., 2021).

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

Changes in connectivity have not been directly linked to electrical activity per se, but neuronal activity is essential to trigger complex molecular signaling cascades, which mediate to the corresponding structural changes. In many cases, calcium signaling is used as a surrogate measure of electrical activity at the synapse as postsynaptic calcium level is largely dictated by neuronal activity. However, the detailed relation between calcium, activity, and spine dynamics is more complex, as the calcium level is also regulated by other signals such as neurotrophins and adhesion molecules (Stoop and Poo, 1996; Bixby et al., 1994).

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

Although activity dependent alterations in synaptic structure occur in both males and females, hormones can modulate their extent, serving to stabilize connections in some cases, while destabilizing and eliminating connections in others. Other hormonal systems, notably glucocorticoids can modulate activity-dependent structural change.

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

The connection between activity and structural change is well documented and the nature of the structural alteration can be growth and stabilization or destabilization and elimination at the synaptic level. Elimination of entire neurons can occur in complete absence of activity, while at the same time, absence of activity can trigger growth of adjacent neurons to a denervated site.

Time-scale
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

Seconds to minutes, hours to days, days to weeks, mature and immature organisms

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

There are currently no known Feedforward/Feedback loops influencing this KER.

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

This KER is supported from rodent models, in which hippocampal brain slices have been studied ex vivo. Despite the hippocampus is structurally quite different among mammals, birds and reptiles, its function in spatial memory is highly conserved (Striedter, 2016). This suggests, with some uncertainty, that this KER is also applicable to multiple species.

Activity-dependent alterations in brain connectivity and synaptic structure occurs in males and females, in all mammals, at all life stages, and is especially prominent during development. Structural remodeling also occurs in the non-mammalian species.

References

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

Andreae LC, Burrone J. The role of neuronal activity and transmitter release on synapse formation. Curr Opin Neurobiol. 2014 Aug;27(100):47-52. doi: 10.1016/j.conb.2014.02.008

Andreae LC, Burrone J. The role of spontaneous neurotransmission in synapse and circuit development. J Neurosci Res. 2018 Mar;96(3):354-359. doi: 10.1002/jnr.24154

Anosike NL, Adejuwon JF, Emmanuel GE, Adebayo OS, Etti-Balogun H, Nathaniel JN, Omotosho OI, Aschner M, Ijomone OM. Necroptosis in the developing brain: role in neurodevelopmental disorders. Metab Brain Dis. 2023 Mar;38(3):831-837. doi: 10.1007/s11011-023-01203-9

Bixby JL, Grunwald GB, Bookman RJ. Ca2+ influx and neurite growth in response to purified N-cadherin and laminin. J Cell Biol. 1994 Dec;127(5):1461-75. doi: 10.1083/jcb.127.5.1461

Bonnycastle K, Davenport EC, Cousin MA. Presynaptic dysfunction in neurodevelopmental disorders: Insights from the synaptic vesicle life cycle. J. Neurochem. 2021; 157: 179–207. https://doi.org/10.1111/jnc.15035

Cherubini E, Di Cristo G, Avoli M. Dysregulation of GABAergic Signaling in Neurodevelomental Disorders: Targeting Cation-Chloride Co-transporters to Re-establish a Proper E/I Balance. Front Cell Neurosci. 2022 Jan 5;15:813441. doi: 10.3389/fncel.2021.813441

Chun SK, Sun W, Park JJ, Jung MW. Enhanced proliferation of progenitor cells following long-term potentiation induction in the rat dentate gyrus. Neurobiol Learn Mem. 2006 Nov;86(3):322-9. doi: 10.1016/j.nlm.2006.05.005. Epub 2006 Jul 7. PMID: 16824772.

Chun SK, Sun W, Jung MW. LTD induction suppresses LTP-induced hippocampal adult neurogenesis. Neuroreport. 2009 Sep 23;20(14):1279-83. doi: 0.1097/WNR.0b013e3283303794. PMID: 1963358

Cohan CS, Kater SB,1986. Suppression of neurite elongation and growth cone motility by electrical activity. Science,27;232(4758):1638-40. doi: 10.1126/science.3715470

Faust TE, Gunner G, Schafer DP,2021. Mechanisms governing activity-dependent synaptic pruning in the developing mammalian CNS. Nat Rev Neurosci 22, 657–673. https://doi.org/10.1038/s41583-021-00507-y

Fauth M, Tetzlaff C. Opposing Effects of Neuronal Activity on Structural Plasticity. Front Neuroanat. 2016 Jun 28;10:75. doi: 10.3389/fnana.2016.00075

Fishbein I, Segal M. Miniature synaptic currents become neurotoxic to chronically silenced neurons. Cereb Cortex. 2007 Jun;17(6):1292-306. doi: 10.1093/cercor/bhl037

Geinisman Y, Morrell F, deToledo-Morrell L. Increase in the relative proportion of perforated axospinous synapses following hippocampal kindling is specific for the synaptic field of stimulated axons. Brain Res. 1990 Jan 22;507(2):325-31. doi: 10.1016/0006-8993(90)90291-i

Gilbert J, O'Connor M, Templet S, Moghaddam M, Di Via Ioschpe A, Sinclair A, Zhu LQ, Xu W, Man HY. NEXMIF/KIDLIA Knock-out Mouse Demonstrates Autism-Like Behaviors, Memory Deficits, and Impairments in Synapse Formation and Function. J Neurosci. 2020 Jan 2;40(1):237-254. doi: 10.1523/JNEUROSCI.0222-19.2019

Graziane N, Dong Y. (2022). Isolation of Synaptic Current. In: Graziane N, Dong Y (eds) Electrophysiological analysis of synaptic transmission. Neuromethods, vol 187. Humana, New York, NY, 2022, pp 101–110 (https://doi.org/10.1007/978-1-0716-2589-7_8)

Hestrin S,2011. Neuroscience. The strength of electrical synapses. Science,21;334(6054):315-6. doi: 10.1126/science.1213894

Hofer SB, Mrsic-Flogel TD, Bonhoeffer T, Hübener M. (2009). Experience leaves a lasting structural trace in cortical circuits. Nature 457,313–317.doi:10.1038/nature07487

Kirov SA, Goddard CA, Harris KM. Age-dependence in the homeostatic upregulation of hippocampal dendritic spine number during blocked synaptic transmission. Neuropharmacology. 2004 Oct;47(5):640-8. doi: 10.1016/j.neuropharm.2004.07.039

Kirov SA, Harris KM. Dendrites are more spiny on mature hippocampal neurons when synapses are inactivated. Nat Neurosci. 1999 Oct;2(10):878-83. doi: 10.1038/13178. 

Maletic-Savatic M, Malinow R, Svoboda K. Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity. Science. 1999 Mar 19;283(5409):1923-7. doi: 10.1126/science.283.5409.1923 

O'Neill K, Musgrave IF, Humpage A. Extended Low-Dose Exposure to Saxitoxin Inhibits Neurite Outgrowth in Model Neuronal Cells. Basic Clin Pharmacol Toxicol. 2017 Apr;120(4):390-397. doi: 10.1111/bcpt.12701

Pan Y and Monje M,2020. Activity Shapes Neural Circuit Form and Function: A Historical Perspective. Journal of Neuroscience, 40 (5) 944-954. https://doi.org/10.1523/JNEUROSCI.0740-19.2019

Stoop R, Poo MM. Synaptic modulation by neurotrophic factors: differential and synergistic effects of brain-derived neurotrophic factor and ciliary neurotrophic factor. J Neurosci. 1996 May 15;16(10):3256-64. doi: 10.1523/JNEUROSCI.16-10-03256.1996

Striedter GF.  Evolution of the hippocampus in reptiles and birds.  J Comp Neurol. 2016 Feb 15;524(3):496-517 

Vees AM, Micheva KD, Beaulieu C, Descarries L. Increased number and size of dendritic spines in ipsilateral barrel field cortex following unilateral whisker trimming in postnatal rat. J Comp Neurol. 1998 Oct 12;400(1):110-24