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Relationship: 747

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 gene expression, Altered leads to Hippocampal anatomy, Altered

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Hippocampal gene expression, Altered

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Hippocampal anatomy, Altered

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	Evgeniia Kazymova (send email)	Open for citation & comment	WPHA/WNT Endorsed
Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals	adjacent	Moderate	Low	Evgeniia Kazymova (send email)	Under Development: Contributions and Comments Welcome
Thyroid Receptor Antagonism and Subsequent Adverse Neurodevelopmental Outcomes in Mammals	adjacent	Moderate	Low	Evgeniia Kazymova (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 Do not cite	Under Development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			Evgeniia Kazymova (send email)	Open for adoption	Under Development

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
mouse	Mus musculus	Moderate	NCBI
rat	Rattus norvegicus	High	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	Moderate

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 basic biological processes that link gene regulation in the structural formation and function of all organs of the body are similar throughout the developing organism. In the developing brain, genes encode proteins critical for developmental events intrinsic to structural development (e.g., neurogenesis, neuronal migration, synaptogenesis, myelination). The development of the hippocampus is no exception to this general rule of biology.

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

The overall weight of evidence is moderate for a direct linkage between perturbation of the expression of genes in brain (and in hippocampus specifically) and neuroanatomical abnormalities. It is widely acknowledged that the development of the structure of the hippocampus is under the control of hippocampal gene expression. However, while an extensive body of literature exists linking some genes to hippocampal structure, there is no complete compendium on the total number of genes involved, nor direct causative links between the myriad of genes and the intricate development (both timing and location) of the majority of hippocampal structure.

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 this KER is rated as strong. It is well established that gene regulation controls brain development. This also applies to the development of the hippocampus, where nuclear thyroid receptors that regulate gene transcription, directly or indirectly via transcription factor regulation, to control translation.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Empirical support for this KER is rated as strong. The number of publications in this area is extensive. A few examples are: Strange et al. (2014); Takei et al. (2016); and Shin et al. (2015). Work supporting the relationship includes use of a variety of animal models (i.e., nutritional deficiencies, chromosome abnormalities, gene deletions, knock out animals, toxicant exposures and developmental hormonal imbalance) (e.g., Frotscher, 2010; Castren and Castren, 2014; Spilker et al., 2016; Skucas et al., 2011; Lessman et al., 2011). Mutant mouse lines generated for genes involved in human cortical malformations such as doublecortin, reelin, Lis1 and Tuba1a also show gross disorganization within the hippocampus (Khalaf-Nazzal et al., 2013). Collectively, data from these studies clearly support the link between alterations in hippocampal gene expression and structural changes in hippocampal volume, cell number, and/or cytoarchitecture. A direct linkage between some specific gene targets and structural change in the hippocampus has been demonstrated using knock out and mutant mouse models (e.g., Grant et al., 1992; Lee et al., 2000; Frotscher, 2010; Castren and Castren, 2014; Spilker et al., 2016; Skucas et al., 2011; Lessman et al., 2011; Khalaf-Nazzal et al., 2013).

Temporal Evidence: The temporal nature of this KER is developmental (Seed et al., 2005). It is a well-recognized fact that there are critical developmental windows for disruption of TR-regulated genes and subsequent formation of the anatomy of the hippocampus. This has been demonstrated in multiple studies. Many of the gene-anatomy relationships critical to brain development only exist during development, or exist only to a very limited extent in the adult brain. For example, genes controlling neuronal proliferation and migration are critically essential in hippocampal development, and their disruption results in abnormal hippocampal anatomy. Whereas, in the adult brain the genes are largely without effect as these processes are completed in the early neonatal period. In support of this, a limited number of studies have defined critical periods for the interaction of some genes and resulting neuroanatomical organization of the hippocampus (Lee et al., 2015; Favaro et al., 2009; Lee et al., 2000). In addition, there are some ‘rescue’ experiments for a select number of genes (eg., Lee et al., 2015; Spilker et al., 2016). Several examples are described below:

In the Jacob/Nsfm knockout model, hippocampal dysplasia is seen in hippocampal areas CA1 and CA3, characterized by reduced complexity of the synapto-dendritic cytoarchitecture, shorter dendrites and fewer branches (Spilker et al., 2016). Simplified dendritic trees and reduced synaptogenesis were also observed in hippocampal primary neurons cultured from these knock out mice relative to cultures from wild type mice. The protein product of Jacob/Nsfm regulates activity-dependent brain-derived neurotrophic factor (Bdnf) transcription. Lower BDNF levels were seen in area CA1 of knock out mice on postnatal day 10. The dysplasia seen in hippocampal neuronal cultures from knock mice could be reversed by BDNF supplementation if administered in early (2-4 days in vitro) but not later (15 days in vitro) in development.

Neuroregluin-2 (Nrg2) contributes to synaptogenesis of the granule cell layer of the hippocampus. In hippocampal slice cultures, inducible microRNA targeting strategies have demonstrated early suppression of Nrg2 (4 days in vitro) but not late suppression (7 days in vitro) reduced synaptogenesis of inhibitory neurons. On the other hand, late treatment impaired the dendritic outgrowth of excitatory synaptic connections. These effects could be eliminated with overexpression of Nrg2 (Lee et al., 2015).

Many of the gene-regulated processes involved in hippocampal development are also present in the developing cortex. In models of prenatal hypothyroidism, altered expression patterns of many genes involved in neuronal migration and apoptosis are associated with disruptions in hippocampal organization and cytoarchitecture of the cerebral cortex (Pathak et al, 2011; Mohan et al., 2012; Lui et al., 2010). Structural changes in hippocampus and cerebral cortex are dependent on time of exposure (Auso et al., 2003; Berbel et al., 2010; Pathak et al., 2011) and can be reversed with TH supplementation (Mohan et al., 2012; Pathak et al., 2011; Berbel et al., 2010).

Dose-Response Evidence: Dose-response data is lacking for this KER. Papers that utilize knock-out and mutant models do not provide ‘dose-response’ information for gene-anatomy relationships. Studies in which genes and anatomy were reported following developmental hypothyroidism were single high-dose studies that focused on varying the developmental window of exposure, but not necessarily the dose.

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 some uncertainties. Few studies exist that report both gene expression changes and structural changes in the hippocampus in same study to provide direct causative evidence for this KER. Lacking also is the specific suite of genes that are altered in the hippocampus at particular developmental times that are causal to the structural defects reported. For future research, it is critical to generate data in which the upstream KE is modulated in a ‘dose-response’ manner to better support the causative relationship. Significant data gaps also exist for basic fetal hippocampal development.

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

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

There are no data on the quantitative linkages between gene expression changes and altered hippocampal anatomy.

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

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

The majority of data in support of this KER is from rodent models. The evolutionary conservation of thyroid receptors (Holzer et al., 2017) coupled with their role in TR regulated gene transcription in neurodevelopment, suggests that this KER may also be applicable to other species.

References

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

Auso E, Lavado-Autric R, Cuevas E, Del Rey FE, Morreale De Escobar G, Berbel P (2004) A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration. Endocrinology 145:4037-4047.

Berbel P, Navarro D, Ausó E, Varea E, Rodríguez AE, Ballesta JJ, Salinas M, Flores E, Faura CC, de Escobar GM. Role of late maternal thyroid hormones in cerebral cortex development: an experimental model for human prematurity. Cereb Cortex. 2010 20(6):1462-75.

Castrén ML, Castrén E. BDNF in fragile X syndrome. Neuropharmacology. 2014 76:729-36.

Favaro R, Valotta M, Ferri AL, Latorre E, Mariani J, Giachino C, Lancini C, Tosetti V, Ottolenghi S, Taylor V, Nicolis SK. Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh. Nat Neurosci. 2009 12(10):1248-56.

Frotscher M. Role for Reelin in stabilizing cortical architecture. Trends Neurosci. 2010 Sep;33(9):407-14.

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.

Holzer G, Roux N, Laudet V. Evolution of ligands, receptors and metabolizing enzymes of thyroid signaling. Mol Cell Endocrinol. 2017 Mar 22. pii: S0303-7207(17)30191-0. doi: 10.1016/j.mce.2017.03.021. [Epub ahead of print]

Khalaf-Nazzal R, Bruel-Jungerman E, Rio JP, Bureau J, Irinopoulou T, Sumia I, Roumegous A, Martin E, Olaso R, Parras C, Cifuentes-Diaz C, Francis F. Organelle and cellular abnormalities associated with hippocampal heterotopia in neonatal doublecortin knockout mice. PLoS One. 2013 Sep 2;8(9):e72622.

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 GABAergicSynapses and Maturation of Glutamatergic Synapses in Newborn Granule Cells ofPostnatal Hippocampus. J Neurosci. 2015 Dec 16;35(50):16479-93.

Lee SM, Tole S, Grove E, McMahon AP. A local Wnt-3a signal is required fordevelopment of the mammalian hippocampus. Development. 2000 Feb;127(3):457-67.

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.

Liu D, Teng W, Shan Z, Yu X, Gao Y, Wang S, Fan C, Wang H, Zhang H.The effect of maternal subclinical hypothyroidism during pregnancy on brain development in rat offspring. Thyroid. 2010 Aug;20(8):909-15.

Mohan V, Sinha RA, Pathak A, Rastogi L, Kumar P, Pal A, Godbole MM (2012) Maternal thyroid hormone deficiency affects the fetal neocorticogenesis by reducing the proliferating pool, rate of neurogenesis and indirect neurogenesis. Exp Neurol 237:477-488.

Pathak A, Sinha RA, Mohan V, Mitra K, Godbole MM. 2011. Maternal thyroid hormone before the onset of fetal thyroid function regulates reelin and downstream signaling cascade affecting neocortical neuronal migration. Cerebral Cortex.11-21.

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, Patton DE. Overview: Using mode of action and life stage information to evaluate the human relevance of animal toxicity data. Crit Rev Toxicol. 2005 35(8-9):664-72.

Shin JH, Kim YN, Kim IY, Choi DH, Yi SS, Seong JK. Increased Cell Proliferations and Neurogenesis in the Hippocampal Dentate Gyrus of Ahnak Deficient Mice. Neurochem Res. 2015 Jul;40(7):1457-62.

Skucas VA, Mathews IB, Yang J, Cheng Q, Treister A, Duffy AM, Verkman AS, Hempstead BL, Wood MA, Binder DK, Scharfman HE. Impairment of select forms ofspatial memory and neurotrophin-dependent synaptic plasticity by deletion ofglial aquaporin-4. J Neurosci. 2011 31(17):6392-7.

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, Kreutz MR.A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impared BDNFSignaling in Dendritogenesis. PLoS Genet. 2016 Mar 15;12(3):e1005907

Strange BA, Witter MP, Lein ES, Moser EI. Functional organization of the hippocampal longitudinal axis. Nat Rev Neurosci. 2014 Oct;15(10):655-69.

Takei Y, Kikkawa YS, Atapour N, Hensch TK, Hirokawa N. Defects in Synaptic Plasticity, Reduced NMDA-Receptor Transport, and Instability of Postsynaptic Density Proteins in Mice Lacking Microtubule-Associated Protein 1A. J Neurosci. 2015 35(47):15539-54.