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Relationship: 203

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

Altered, Neuroanatomy leads to Altered, Neurophysiology

Upstream event

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

Altered, Neuroanatomy

Downstream event

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

Altered, Neurophysiology

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
XX Inhibition of Sodium Iodide Symporter and Subsequent Adverse Neurodevelopmental Outcomes in Mammals	adjacent	Moderate	Low	Kevin Crofton (send email)	Not under active 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

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

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

Synaptic transmission and plasticity require the integrity of the anatomical substrate. The connectivity of axons emanating from one set of cells to synapse on the dendrties of the receiving cells must be intact for effective communication between neurons to be possible. Changes in the placement of cells within the network due to delays in neuronal migration, the absence of a full proliferation 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. These anatomical alterations are among a host of many structural anomolies reported in various regions of the brain following severe developmental hypothyroidism. Although the primary evidence of synaptic transmission impairments in hypothyroid models have been limited to hippocampus, it is assumed that the role TH play in these processes is likely similar across different brain regions.

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 weight of evidence supporting the relationship between structural abnormalities in brain induced by thyroid hormone insufficiency and altered synaptic function is moderate. Functional change as exemplified by alterations in synaptic transmission may be more easily detected that structural abnormalities. What is less than clear is the exact alignment between the neuroanatomical effects that have been identified with developmental hypothyroidism and the neurophysiological characteristics that have been described in hippocampus.

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 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, synaptogenesis have been described in models of severe hormone deprivation. Because synaptic transmission relies on the integrity of contacts and the reilability of electical and chemical transmission between pre- and post-synaptic neurons, it is well accepted that interference on the anatomical levels will very much impact the functional output on the neurophysiological level.

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

Most of the information on developmental hypothyroidism and altered synaptic function has been provided by study of the hippocampus. Within the hippocampus, area CA1 has been investigated primarily with in vitro techniques, harvesting slices of hippocampus from exposed animals an measuring synaptic function across the Shaeffer Collateral-pyramidal cell synapse (Vara et al., Sui and Gilbert, 2003). Pyramidal neurons of hypothyroid animals have fewer synapses and an impoverished dendritic arbor (Rami et al., 1986; Madeira et al., 1992). The other major region in hippocampus investigated in hpothyroid models is the perforant path-dentate gyrus synapse (Gilbert, 2011).

Granule cells are the principal cell type of the dentate gyrus and receive input from cortical neurons of the entorhinal cortex. TPO inhibitors like PTU and MMI decrease the volume of the granule cell layer, the density of cells within the layer, and estimates of total granule cell number (Madeira et al. 1991). Migration of granule cells from the proliferative zone to the granule cell layer is retarded by thyroid deficiency as is dendritic arborization and synaptogenesis assessed by immunohistochemistry for the synaptic protein, synaptophysin (Rami et al. 1986; Dong et al., 2013).

In models of severe hormone insufficiency, synaptic transmission in both hippocampal subfields is dramatically compromised. Excitatory synaptic function is disrupted in area CA1 of slices taken from hypothyroid animals in the preweaning period (Vara et al., 2002; Sui and Gilbert 2003; Gilbert 2004; Dong et al., 2007). These changes in synaptic transmission are permanent as deficiencies are also evident in slices from adult animals exposed developmentally but tested following return to euthyroidism (Gilbert 2003; Sui et al. 2005). Reductions in the expression of synaptic proteins are associated with these deficites in synaptic transmission (Dong et al., 2013). Expression of the calcium-binding protein, parvalbumin, is reduced in the hippocampus and cortex of PTU-exposed rats and associated with reductions in paired pulse depression in hippocampus, a measure of synaptic inhibition (Gilbert et al., 2007; Berbel et al., 1998). Induction of hypothyroid state in the adult animals does not induce these changes in synaptic function (Gilbert et al., 2007; Sanchez-Heurta et al., 2014).

Deficits in synaptic plasticity in area CA1 have also been reported following developmental TH insufficiency induced by TPO inhibitors by a number of laboratories (Opazo et al., 2008; Dong et al., 2005; Sui and Gilbert, 2003). In the dentate gyrus, most investigations have been performed in intact animals and as such examined primarily in adult offspring of hypothyroid dams. Suppression of excitatory and inhibitory synaptic function and deficits in synaptic plasticity have been demonstrated (Gilbert, 2003; 2011; Gilbert and Sui, 2006; Gilbert et al., 2007).

Evidence of temporal concordance for antomical and neurophysiological deficits induced by TPO inhibition derives from reports of dose-dependent declines in synaptic function with moderate decreases in hormones during development (Gilbert, 2011) and the absence of similar deficiencies when hormone reductions occur in adulthood (Gilbert et al., 2007; Sanchez-Huerta et al., 2014).

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

The uncertainties that exist in the relationship between altered neuroanatomy and altered neurophysiology include the exact way in which a change in cell number, degree of myelination, reduced dendritric arborization and synaptogenesis may express itself neurophysiologically. Dose-dependent reductions in synaptic function in hippocampus have been demonstrated in models of moderate degrees of hormone 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 form the hippocampus.

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

There are insufficient data available to describe the quantitative linkages between altered neuroanatomy and deficits in synaptic transmission and plasticity.

Response-response Relationship

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

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

References

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

Berbel P, et al. Distribution of parvalbumin immunoreactivity in the neocortex of hypothyroid adult rats. Neurosci Lett 1996, 204(1-2), 65-68.

Dong, J., H. Yin, et al. (2005). Congenital iodine deficiency and hypothyroidism impair LTP and decrease C-fos and C-jun expression in rat hippocampus. Neurotoxicology 26(3): 417-26.

Dong J, Wang Y, Wang Y, Wei W, Min H, Song B, Xi Q, Teng W, Chen J. Iodine deficiency increases apoptosis and decreases synaptotagmin-1 and psd-95 in rat hippocampus. Nutritional neuroscience. 2013;16(3):135-141.

Gilbert, M. E. (2004). Alterations in synaptic transmission and plasticity in area CA1 of adult hippocampus following developmental hypothyroidism. Dev Brain Res 148(1): 11-8.

Gilbert ME. Impact of low-level thyroid hormone disruption induced by propylthiouracil on brain development and function. Toxicol Sci. 2011;124(2):432-445.

Gilbert, M. E. and C. Paczkowski (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(1): 19-29.

Gilbert, M. E. and L. Sui (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(1): 10-22.

Gilbert ME, et al. Thyroid hormone insufficiency during brain development reduces parvalbumin immunoreactivity and inhibitory function in the hippocampus. Endocrinology 2007, 148(1), 92-102.

Gilbert, M. E. (2004). Alterations in synaptic transmission and plasticity in area CA1 of adult hippocampus following developmental hypothyroidism. Dev Brain Res 148(1): 11-8.

Gilbert ME, Ramos RL, McCloskey DP, Goodman JH. Subcortical band heterotopia in rat offspring following maternal hypothyroxinaemia: structural and functional characteristics. J Neuroendocrinol. 2014 Aug;26(8):528-41

Gilbert ME, Hedge JM, Valentín-Blasini L, Blount BC, Kannan K, Tietge J, Zoeller RT, Crofton KM, Jarrett JM, Fisher JW. An animal model of marginal iodine deficiency during development: the thyroid axis and neurodevelopmental outcome. Toxicol Sci. 2013 Mar;132(1):177-95.

Madeira, MD, et al. Effects of hypothyroidism upon the granular layer of the dentate gyrus in male and female adult rats: a morphometric study. J Comp Neurol 1991, 314(1), 171-186.

Madeira, M. D., N. Sousa, et al. (1992). "Selective vulnerability of the hippocampal pyramidal neurons to hypothyroidism in male and female rats." J Comp Neurol 322(4): 501-18.

Opazo MC, Gianini A, Pancetti F, Azkcona G, Alarcón L, Lizana R, Noches V, Gonzalez PA, Marassi MP, Mora S, Rosenthal D, Eugenin E, Naranjo D, Bueno SM, Kalergis AM, Riedel CA (2008), Maternal hypothyroxinemia impairs spatial learning and synaptic nature and function in the offspring. Endocrinology 149:5097-5106.

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

Rami, A. and A. Rabie (1988). "Effect of thyroid deficiency on the development of glia in the hippocampal formation of the rat: an immunocytochemical study." Glia 1(5): 337-45.

Sánchez-Huerta K., Pacheco-Rosado J., Gilbert M.E. Adult Onset-Hypothyroidism: Alterations in Hippocampal Field Potentials in the Dentate Gyrus are Largely Associated with Anesthesia-Induced Hypothermia. Journal Neuroendocrinology, 2014

Vara H, et al. Thyroid hormone regulates neurotransmitter release in neonatal rat hippocampus. Neuroscience 2002, 110(1), 19-28.