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Relationship: 358

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Synaptogenesis, Decreased leads to Neuronal network function, Decreased

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. 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

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities adjacent Low Agnes Aggy (send email) Open for citation & comment TFHA/WNT Endorsed
Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment adjacent Low Low Arthur Author (send email) Open for citation & comment TFHA/WNT Endorsed

Taxonomic Applicability

Select one or more structured terms 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. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
mouse Mus musculus High NCBI
Caenorhabditis elegans Caenorhabditis elegans Moderate NCBI
Drosophila melanogaster Drosophila melanogaster Moderate NCBI

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help
Sex Evidence
Mixed High

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help
Term Evidence
During brain development High

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. More help

The ability of a neuron to communicate is based on neural network formation that relies on functional synapse establishment (Colón-Ramos, 2009). The main roles of synapses are the regulation of intercellular communication in the nervous system, and the information flow within neural networks. The connectivity and functionality of neural networks depends on where and when synapses are formed. Therefore, the decreased synapse formation during the process of synaptogenesis is critical and leads to decrease of neural network formation and function in the adult brain.

Synaptic transmission and plasticity require the integrity of the anatomical substrate. The connectivity of axons emanating from one set of cells to post-synaptic side of synapse on the dendrites of the receiving cells must be intact for effective communication between neurons. Changes in the placement of cells within the network due to delays in neuronal migration, the absence of a full formation of dendritic arbors and spine upon which synaptic contacts are made, and the lagging of transmission of electrical impulses due to insufficient myelination will individually and cumulatively impair synaptic function. Since synaptogenesis follows the early neurodevelopmental processes such as neuronal and glial cells proliferation, migration, alterations in dendritic arborisation etc., therefore, it encompasses, possible changes in these early stages of brain development that could also be triggered under hypothyroidism, leading to defective synaptogenesis and resulting in abnormal function of neuronal network function. These anatomical alterations are responsible for many structural anomalies reported in various regions of the brain following severe developmental hypothyroidism. Although the primary evidence of synaptic transmission impairments in hypothyroid models have come from studying the hippocampus, it is assumed that the role thyroid hormones play in these processes is likely similar across different brain regions. Altered hippocampal structure induced by decreased TH levels impacts neurogenesis in the developing hippocampus or cortex, contributing to deficits in synaptic function.

Evidence Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help

The weight of evidence supporting the relationship between decreased synaptogenesis induced by TH insufficiency and altered neuronal network and synaptic function is moderate. Functional change as exemplified by alterations in synaptic transmission may be more easily detected than structural abnormalities. The exact alignment between the neuroanatomical effects (such as decreased synaptogenesis and alteration of GABAergic interneurons) that have been associated with developmental hypothyroidism (e.g., elicited by exposing rat dams to TPO inhibitors) and the neurophysiological impairments has not been entirely elucidated.

Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility 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 (see page 40 of the User Handbook for further information).   More help

Neuronal network formation and function are established via the process of synaptogenesis. The developmental period of synaptogenesis is critical for the formation of the basic circuitry of the nervous system, although neurons are able to form new synapses throughout life (Rodier, 1995). The brain electrical activity dependence on synapse formation is critical for proper neuronal communication.

Alterations in synaptic connectivity lead to refinement of neuronal networks during development (Cline and Haas, 2008). Indeed, knockdown of PSD-95 arrests the functional and morphological development of glutamatergic synapses (Ehrlich et al., 2007).

The biological plausibility of the known effects of TH insufficiency on brain structure having an impact on synaptic function and plasticity in brain is strong. Reductions in myelination of axons, cell number, dendritic arborization, and synaptogenesis have been described in models of severe hormone deprivation, as comprehensively summarized by Thompson and Potter, 2000. Because synaptic transmission relies on the integrity of synaptic contacts and the electrical and chemical transmission between pre- and post-synaptic neurons, it is well accepted that interference with process of synapse formation (morphological unit of neuronal network) will very much impact the neural network function.

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help

The exact mechanism by which a change in cell number, reduced dendritric arborization and synaptogenesis may lead to decreased neuronal network function has not been fully elucidated. Dose-dependent reductions in synaptic function in hippocampus have been demonstrated in models of moderate degrees of TH reduction, but studies of the anatomical integrity of the specific cell populations examined electrophysiologically have largely been evaluated in models of severe hypothyroidism and often in brain regions distinct from the hippocampus.

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help
Time-scale
This sub-section should be used to provide 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?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help
Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help

The main proof of evidence comes from in vivo studies in rodents. However, Colón-Ramos (2009) has recently reviewed the early developmental events that take place during the process of synaptogenesis in invertebrates, pointing out the importance of this process in neural network formation and function. The experimental findings reviewed in this paper derive from knowledge acquired in the field of neuroscience using C. elegans and Drosophila; at the same time, emerging findings derived from vertebrates are also discussed (Colón-Ramos, 2009).

References

List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help

Cline H, Haas K. (2008). The regulation of dendritic arbor development and plasticity by glutamatergic synaptic input: A review of the synaptotrophic hypothesis. J Physiol 586: 1509-1517.

Colón-Ramos DA. (2009). Synapse formation in developing neural circuits. Curr Top Dev Biol. 87: 53-79.

Di Liegro I, Savettieri G, Coppolino M, Scaturro M, Monte M, Nastasi T, Salemi G, Castiglia D, Cesterlli A (1995). Expression of synapsin I gene in primary cultures of differentiating rat cortical neurons. Neurochem. Res., 20, pp. 239–243

Dong J, Yin H, Liu W, Wang P, Jiang Y, Chen J. (2005). Congenital iodine deficiency and hypothyroidism impair LTP and decrease C-fos and C-jun expression in rat hippocampus. Neurotoxicology 26:417-426.

Ehrlich I, Klein M, Rumpel S, Malinow R. (2007). PSD-95 is required for activity-driven synapse stabilization. Proc Natl Acad Sci U S A. 104: 4176-4181.

Gilbert ME. (2004). Alterations in synaptic transmission and plasticity in area CA1 of adult hippocampus following developmental hypothyroidism. Brain Res Dev Brain Res 148:11-18.

Gilbert ME. (2011). Impact of low-level thyroid hormone disruption induced by propylthiouracil on brain development and function. Toxicol Sci 124:432-445.

Gilbert ME, Hedge JM, Valentin-Blasini L, Blount BC, Kannan K, Tietge J, Zoeller RT, Crofton KM, Jarrett JM, Fisher JW. (2013). An animal model of marginal iodine deficiency during development: the thyroid axis and neurodevelopmental outcome. Toxicol Sci 132:177-195.

Gilbert ME, Paczkowski C. (2003). Propylthiouracil (PTU)-induced hypothyroidism in the developing rat impairs synaptic transmission and plasticity in the dentate gyrus of the adult hippocampus. Brain Res Dev Brain Res 145:19-29.

Gilbert ME, Sanchez-Huerta K, Wood C. (2016). Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology 157:774-787.

Gilbert ME, Sui L. (2006). Dose-dependent reductions in spatial learning and synaptic function in the dentate gyrus of adult rats following developmental thyroid hormone insufficiency. Brain Res 1069:10-22.

Gilbert ME, Sui L, Walker MJ, Anderson W, Thomas S, Smoller SN, Schon JP, Phani S, Goodman JH. (2007). Thyroid hormone insufficiency during brain development reduces parvalbumin immunoreactivity and inhibitory function in the hippocampus. Endocrinology 148:92-102.

Herdegen T, Skene P, Bahr M (1997). The c-Jun transcription factor-bipotential mediator of neuronal death, survival and regeneration. Trends Neurosci, 20, pp. 227–231

Kumar MV, Desiraju T. (1992). EEG spectral power reduction and learning disability in rats exposed to lead through postnatal developing age. Indian J Physiol Pharmacol. 36: 15-20.

Madeira MD, Cadete-Leite A, Andrade JP, Paula-Barbosa MM. (1991). Effects of hypothyroidism upon the granular layer of the dentate gyrus in male and female adult rats: a morphometric study. J Comp Neurol 314:171-186.

Madeira MD, Sousa N, Lima-Andrade MT, Calheiros F, Cadete-Leite A, Paula-Barbosa MM. (1992). Selective vulnerability of the hippocampal pyramidal neurons to hypothyroidism in male and female rats. J Comp Neurol 322:501-518.

McCarren M, Eccles CU. (1983). Neonatal lead exposure in rats: II. Effects on the hippocampal afterdischarge. Neurobehav Toxicol Teratol. 5: 533-540.

Otto D, Reiter L. (1984). Developmental changes in slow cortical potentials of young children with elevated body lead burden. Neurophysiological considerations. Ann N Y Acad Sci. 425: 377-383.

Rami A, Patel AJ, Rabie A. (1986a). Thyroid hormone and development of the rat hippocampus: morphological alterations in granule and pyramidal cells. Neuroscience 19:1217-1226.

Rami A, Rabie A, Patel AJ. (1986b). Thyroid hormone and development of the rat hippocampus: cell acquisition in the dentate gyrus. Neuroscience 19:1207-1216.

Rami A, Rabie A. (1990). Delayed synaptogenesis in the dentate gyrus of the thyroid-deficient developing rat. Dev Neurosci 12:398-405.

Rodier PM. (1995). Developing brain as a target of toxicity. Environ. Health Perspect. 103: 73-76.

Sui L, Anderson WL, Gilbert ME. (2005). Impairment in short-term but enhanced long-term synaptic potentiation and ERK activation in adult hippocampal area CA1 following developmental thyroid hormone insufficiency. Toxicol Sci 85:647-656.

Sui L, Gilbert ME. (2003). Pre- and postnatal propylthiouracil-induced hypothyroidism impairs synaptic transmission and plasticity in area CA1 of the neonatal rat hippocampus. Endocrinology 144:4195-4203.

Taylor MA, Swant J, Wagner JJ, Fisher JW, Ferguson DC. (2008). Lower thyroid compensatory reserve of rat pups after maternal hypothyroidism: correlation of thyroid, hepatic, and cerebrocortical biomarkers with hippocampal neurophysiology. Endocrinology 149:3521-3530.

Thompson CC, Potter GB. (2000). Thyroid hormone action in neural development. Cereb Cortex. Oct;10(10):939-45.

Vara H, Martinez B, Santos A, Colino A. (2002). Thyroid hormone regulates neurotransmitter release in neonatal rat hippocampus. Neuroscience 110:19-28.