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Relationship: 749

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

Hippocampal anatomy, Altered leads to Hippocampal Physiology, 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
Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals adjacent Moderate Low Kevin Crofton (send email) Open for citation & comment WPHA/WNT Endorsed
Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals adjacent Moderate Low Mary Gilbert (send email) Under Development: Contributions and Comments Welcome
Thyroid Receptor Antagonism and Subsequent Adverse Neurodevelopmental Outcomes in Mammals adjacent Moderate Low Kevin Crofton (send email) Under development: Not open for comment. Do not cite Under Development
Upregulation of Thyroid Hormone Catabolism via Activation of Hepatic Nuclear Receptors, and Subsequent Adverse Neurodevelopmental Outcomes in Mammals adjacent Katie Paul Friedman (send email) Open for adoption Under Development
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
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

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

The hippocampus is a highly integrated and organized communication and information processing network with millions of interconnections among its constitutive neurons (see Andersen et al, 2006). Neuronal spines are the primary site of action for synaptic interface between neurons. Although difficult to measure due to their small size, large number and variable shapes, changes in the frequency and structure of dendritic spines of hippocampal neurons has dramatic effects on synaptic physiology and plasticity (Harris et al., 1984). Anatomical integrity at a more macro-level is also essential for physiological function. The connectivity of axons emanating from one set of cells that synapse on the dendrites of the receiving cells must be intact for effective communication between neurons to be possible. Synaptogenesis is a critical step for neurons to be integrated into neural networks during development. Changes in the placement of cells within the network due to delays or alterations in neuronal migration, the absence of a full proliferation of dendritic arbors and spines upon which synaptic contacts are made, and the lagging of transmission of electrical impulses (e.g., due to insufficient myelination) will independently and cumulatively impair synaptic function.

It is also well documented that at the molecular level (mainly based on studies in genetically modified mouse models summarized in Appendix C table) that disruption in the expression of pre- and post-synaptic proteins involved in the presynaptic vesicular docking, fusion or release of neurotransmitters impair stabilization of synapses during development. This ultimately alters cytoarchitecture at the macro and ultrastructural level and leads to modification in the physiological integrity of neural circuits in the mature brain. The functional impact of these macro- and micro- alterations hippocampus at the structural level are most often revealed by deficits in neurotransmission and activity-dependent plasticity. 

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

Most of the text in this KER was reviewed and revised as part of the OECD AOP project and approved in 2019. This text was developed using standard literature search procedures set to identify any links between anatomical changes in the hippocampus and subsequent changes in hippocampal physiology.  The most important resulting papers were identified as having measured both KE5 and KE6.  This was updated by a recent systematic search conducted by EFSA in 2021 and 2022 (see Appendix B of EFSA technical report, 2024).  Additional papers, including those using gene models, were identified, and added to the text.

Evidence Supporting this KER

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

The weight of evidence supporting the relationship between structural abnormalities in brain induced and altered synaptic function is moderate. There is no doubt that altered structure can lead to altered function. Many examples from knock out models, genetic mutations, prenatal alcohol, nutritional deficits demonstrate a correlative link between altered structure and impaired synaptic function within the hippocampus (Gil-Mohapel et al., 2010; Berman and Hannigan, 2000; Grant et al., 1992; Palop et al., 2010; Ieraci and Herrera, 2007). However, the scientific understanding of the causative and quantitative relationship between the two KEs is incomplete. 

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 alterations in hippocampal structure impacting synaptic function and plasticity in the brain is strong. Because synaptic transmission in the hippocampus relies on the integrity of contacts and the reliability of electrical and chemical transmission between pre- and post-synaptic neurons, it is well accepted that interference on the anatomical levels will largely impact the functional output on the neurophysiological level (Knowles, 1992; Schultz and Engelhardt, 2014). 

Extensive research has provided substantial data on the characteristics supporting a direct link between alterations in neuronal anatomy (axon and dendritic spines morphology, shape and density, vesicular proteins and release, synaptogenesis and neuronal network formation) and neurotransmission, particularly in the context of activity-dependent changes in synaptic strength (synaptic plasticity), best exemplified in the phenomenon of long-term potentiation (LTP). For instance, spine structure is closely linked to synapse function, as the size of spine heads scales with synaptic strength (Matsuzaki et al., 2001; Noguchi et al., 2011). Moreover, the shape and number of spines can be modified by the induction of synaptic plasticity (Matsuzaki et al., 2001; Tønnesen et al., 2014; Zhou et al., 2004).  These anatomical alterations in hippocampus lead to changes in the electrophysiological properties of this brain region. Specifically, they serve as physiological readouts of hippocampal function at the synaptic level. The most common physiological readouts were revealed as impairments in basal neurotransmission, synaptic inhibition, and synaptic plasticity (LTP and LTD) (Schnell et al.,2002; Ehrlich & Malinow, 2004; Schmeisser et al., 20129). As detailed in KER4, these same activity-dependent processes are invoked as mechanistic underpinnings for how neuronal activity affects structure, particularly in the developing brain.

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

There are no inconsistencies in this KER, but there are uncertainties. Although several examples are evident to demonstrate direct linkages between alterations in hippocampal anatomy and disruptions in hippocampal physiology, there is not a common cellular mechanism, anatomical insult, or signature pattern of synaptic impairment that defines a common anatomically driven physiological phenotype.  In addition, it is also known that there is an interaction between physiological and anatomical development, where anatomy develops first, and can be ‘reshaped’ by the ongoing maturation of physiological function (e.g., Kutsarova et al., 2017). The scientific understanding of the causative, interactive, and quantitative relationship between the two KEs is currently incomplete. 

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

There are currently no known modulating factors.

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

Although there are several examples of direct links between changes in hippocampal anatomy and disruptions in hippocampal physiology, there is not one mechanism, one anatomical insult, or one signature pattern of synaptic impairment that accompanies each of these treatments. Information does not exist to develop quantitative relationships between the KEs in this KER. Publications that utilize knock-out and mutant models have not provided ‘dose-response’ information for anatomy-physiology relationships.

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
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

Most data in support of this KER are from rodent models, supported by limited evidence in humans.  The evolutionary conservation of hippocampal anatomy in mammals, birds, and reptiles (see Hevner, 2016; Streidter, 2015) suggests, with some uncertainty, that this KER is also applicable to multiple species.

References

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

Andersen, P., Morris,R., Amaral,D., Bliss,T., O'Keefe, J. (Editors). The Hippocampus Book. Oxford University Press, 2006.  ISBN: 9780195100273 

Berman RF, Hannigan JH. Effects of prenatal alcohol exposure on the hippocampus: spatial behavior, electrophysiology, and neuroanatomy. Hippocampus. 2000;10(1):94-110. 

Bruel-Jungerman E, Davis S, Laroche S (2007) Brain plasticity mechanisms and memory: a party of four. Neuroscientist 13:492-505. 

Bruel-Jungerman E, Veyrac A, Dufour F, Horwood J, Laroche S, Davis S (2009) Inhibition of PI3K-Akt signaling blocks exercise-mediated enhancement of adult neurogenesis and synaptic plasticity in the dentate gyrus. PLoS ONE 4(11): e7901. doi:10.1371/journal.pone.000790

Deng, W., Aimone, J. & Gage, F. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory?. Nat Rev Neurosci 11, 339–350 (2010). https://doi.org/10.1038/nrn2822

Ehrlich I, Malinow R (2004), Postsynaptic Density 95 controls AMPA Receptor Incorporation during Long-Term Potentiation and Experience-Driven Synaptic Plasticity. J Neurosci 24:916–927 

Ehrlich I, Klein M, Rumpel S, Malinow R. 2007, PSD-95 is required for activity-driven synapse stabilization PNAS, 104, 4176–4181 

Gilbert ME, Goodman JH, Gomez J, Johnstone AF, Ramos RL. Adult hippocampal neurogenesis is impaired by transient and moderate developmental thyroid hormone disruption. Neurotoxicology. 2016 Dec 31;59:9-21. 

Gil-Mohapel J, Boehme F, Kainer L, Christie BR. Hippocampal cell loss and neurogenesis after fetal alcohol exposure: insights from different rodent models.Brain Res Rev. 2010 Sep 24;64(2):283-303. 

Grant SG, O'Dell TJ, Karl KA, Stein PL, Soriano P, Kandel ER. Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science. 1992 Dec 18;258(5090):1903-10. 

Harris KM, Teyler TJ. Developmental onset of long-term potentiation in area CA1 of the rat hippocampus. J Physiol. 1984 Jan;346:27-48. 

Herrera DG, Yague AG, Johnsen-Soriano S, Bosch-Morell F, Collado-Morente L, Muriach M, Romero FJ, Garcia-Verdugo JM (2003) Selective impairment of hippocampal neurogenesis by chronic alcoholism: protective effects of an antioxidant. Proc Natl Acad Sci U S A 100:7919-7924. 

Hevner RF. Evolution of the mammalian dentate gyrus. J Comp Neurol. 2016 524(3):578-94. 

Hosokawa T., Rusakov DA, Bliss TVP, and Fine A: Repeated Confocal Imaging of Individual Dendritic Spines in the Living Hippocampal Slice: Evidence for Changes in Length and Orientation Associated with Chemically Induced LTP. The Journal of Neuroscience, August 1995, 75(8): 5580-5573

Ieraci A, Herrera DG. Single alcohol exposure in early life damages hippocampal stem/progenitor cells and reduces adult neurogenesis. Neurobiol Dis. 2007 Jun;26(3):597-605. 

Kameda M, Taylor CJ, Walker TL, Black DM, Abraham WC, Bartlett PF (2012) Activation of latent precursors in the hippocampus is dependent on long-term potentiation. Transl Psychiatry 2:e72. 

Kapoor R, Fanibunda SE, Desouza LA, Guha SK, Vaidya VA (2015) Perspectives on thyroid hormone action in adult neurogenesis. J Neurochem 133:599-616. 

Knowles WD, Normal anatomy and neurophysiology of the hippocampal formation. J Clin Neurophysiol. 1992 Apr;9(2):252-63. 

Kutsarova E, Munz M, Ruthazer ES.  Rules for Shaping Neural Connections in the Developing Brain.  Front Neural Circuits. 2017. 10:111. doi: 10.3389/fncir.2016.00111. 

Lee KH, Lee H, Yang CH, Ko JS, Park CH, Woo RS, Kim JY, Sun W, Kim JH, Ho WK, Lee SH. Bidirectional Signaling of Neuregulin-2 Mediates Formation of GABAergic Synapses and Maturation of Glutamatergic Synapses in Newborn Granule Cells ofPostnatal Hippocampus. J Neurosci. 2015 Dec 16;35(50):16479-93. 

Lessmann V, Stroh-Kaffei S, Steinbrecher V, Edelmann E, Brigadski T, Kilb W, Luhmann HJ. The expression mechanism of the residual LTP in the CA1 region of BDNF k.o. mice is insensitive to NO synthase inhibition. Brain Res. 2011. 1391:14-23. 

Matsuzaki M, Ellis-Davies GC, Nemoto T, Miyashita Y, Iino M, Kasai H. Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nat Neurosci. 2001 Nov;4(11):1086-92. 

Montero-Pedrazuela A, Venero C, Lavado-Autric R, Fernandez-Lamo I, Garcia-Verdugo JM, Bernal J, Guadano-Ferraz A (2006) Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior. Mol Psychiatry 11:361-371. 

Noguchi J, Nagaoka A, Watanabe S, Ellis-Davies GC, Kitamura K, Kano M, Matsuzaki M, Kasai H. In vivo two-photon uncaging of glutamate revealing the structure-function relationships of dendritic spines in the neocortex of adult mice. J Physiol. 2011 May 15;589(Pt 10):2447-57. 

Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron. 2007 Sep 6;55(5):697-711. 

Panja, D. and C. R. Bramham (2014). "BDNF mechanisms in late LTP formation: A synthesis and breakdown." Neuropharmacology 76 Pt C: 664-676.Schultz C, Engelhardt M. Anatomy of the hippocampal formation. Front Neurol Neurosci. 2014. 34:6-17 

Saxe MD, Battaglia F, Wang JW, Malleret G, David DJ, Monckton JE, Garcia AD, Sofroniew MV, Kandel ER, Santarelli L, Hen R, Drew MR. Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17501-6. 

Schmeisser MJ, Baumann B, Johannsen S, Vindedal GF, Jensen V, Hvalby OC, Sprengel R, Seither Maqbool A, Magnutzki A, Lattke M, Oswald F, Boecker TM, Wirth T. 2012, Cellular/Molecular IB Kinase/Nuclear Factor B-Dependent Insulin-Like Growth Factor 2 (Igf2) Expression Regulates Synapse Formation and Spine Maturation via Igf2 Receptor Signaling.  The Journal of Neuroscience: 32(16):5688 –5703 

Schnell E, Sizemore M, Karimzadegan S, Chen L, Bredt DS, Nicoll RA (2002),  Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number Proc Natl Acad Sci USA 99:13902–13907. 

Schultz C, Engelhardt M.  Anatomy of the hippocampal formation.  Front Neurol Neurosci. 2014. 4:6-17. 

Seed J, Carney EW, Corley RA, Crofton KM, DeSesso JM, Foster PM, Kavlock R, Kimmel G, Klaunig J, Meek ME, Preston RJ, Slikker W Jr, Tabacova S, Williams GM, Wiltse J, Zoeller RT, Fenner-Crisp P and Patton DE, 2005.  Overview: Using mode of action and life stage information to evaluate the human relevance of animal toxicity data. Critical reviews in toxicology , 35:664-72. 

Spilker C, Nullmeier S, Grochowska KM, Schumacher A, Butnaru I, Macharadze T, Gomes GM, Yuanxiang P, Bayraktar G, Rodenstein C, Geiseler C, Kolodziej A, Lopez-Rojas J, Montag D, Angenstein F, Bär J, D'Hanis W, Roskoden T, MikhaylovaM, Budinger E, Ohl FW, Stork O, Zenclussen AC, Karpova A, Schwegler H and Kreutz MR,2016.  A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impaired BDNFSignaling in Dendritogenesis. PLoS Genetics. 12(3): e1005907. https://doi.org/10.1371/journal.pgen.1005907 

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

Tønnesen J, Katona G, Rózsa B, Nägerl UV. Spine neck plasticity regulates compartmentalization of synapses. Nat Neurosci. 2014 May;17(5):678-85. 

Triviño-Paredes J, Patten AR, Gil-Mohapel J, Christie BR. The effects of hormones and physical exercise on hippocampal structural plasticity. Front Neuroendocrinol. 2016. 41:23-43. 

Zhou Q, Koichi J.Homma KJ, Poo M., 2004, Shrinkage of Dendritic Spines Associated with Long-Term Depression of Hippocampal Synapses. Neuron, 44 (5):749-757