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TH synthesis, Decreased leads to Impairment, Learning and memory
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment||non-adjacent||High||Moderate||Arthur Author (send email)||Open for citation & comment||TFHA/WNT Endorsed|
Life Stage Applicability
|During brain development||High|
Key Event Relationship Description
It is widely accepted that the thyroid hormones (TH) play a prominent role in the development and function of the CNS, including hippocampus and neocortex, two critical brain structure closely linked to the cognitive function (Gilbert et al., 2012). Brain concentrations of T4 are dependent on transfer of T4 from serum, through the vascular endothelia, into astrocytes. In astrocytes, T4 is converted to T3 by deiodinase and subsequently transferred to neurons cellular membrane transporters. In the brain T3 controls transcription and translation of genes responsible for normal hippocampal structural and functional development. Normal hippocampal structure and physiology are critical for the development of cognitive function. Thus, there is an indisputable indirect link between TH synthesis, controlling the levels of T4 in serum, and cognitive function, including learning and memory processes.
Evidence Supporting this KER
The weight of evidence supporting the relationship between decreased TH synthesis and learning and memory impairments (occurring as a consequence of altered neuronal network and synaptic function) is strong (Vara et al., 2002; Sui and Gilbert, 2003, 2004, 2011;Dong et al., 2005; Sui et al., 2005). This is consistent with the well understood and documented relationship between TH synthesis that is responsible for TH concentrations in serum, and consequently in brain. TH controls brain development and function, including learning and memory processes, in humans and animals.
The importance of thyroid hormones (TH) in brain development has been recognised and investigated for many decades (Bernal, 2011; Williams 2008). Several human studies have shown that low levels of circulating maternal TH (as a consequence of a decrease of TH synthesis) can lead to neurophysiological deficits in the offspring, including learning and memory deficits, or even cretinism in most severe cases (Zoeller and Rovet, 2004; Henrichs et al., 2010).
Uncertainties and Inconsistencies
Numerous studies reported that iodine deficiency in critical periods of brain development and growth causes severe and permanent growth and cognitive impairment (cretinism) (Pesce and Kopp, 2014; de Escobar et al., 2007; de Escobar et al., 2008; Zimmermann, 2007; Melse-Boonstra and Jaiswal, 2010; Horn and Heuer, 2010; Zimmermann, 2012). However, direct quantitative correlation between decreased TH synthesis (as a consequence of TPO inhibition) and decreased cognition, in support to this KER, were not assessed in these reports.
Moreover, Wheeler et al., 2012 used fMRI visuospatial memory task to assess hippocampal activation in adolescents with CH (N = 14; age range, 11.5-14.7 years) compared with controls (N = 15; age range, 11.2-15.5 years). Despite, adolescents with congenital hypothyroidism showed both increased magnitude of hippocampal activation relative to controls and bilateral hippocampal activation when only the left was observed in controls, no group differences were recorded in task performance.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Deficiencies in learning and memory following developmental hypothyroidism (TH synthesis inhibition) have been documented mainly in rodents and humans.
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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.
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Berbel P, Navarro D, Auso E, Varea E, Rodriguez AE, Ballesta JJ, Salinas M, Flores E, Faura CC, de Escobar GM. (2010). Role of late maternal thyroid hormones in cerebral cortex development: an experimental model for human prematurity. Cereb Cortex 20:1462-1475.
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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.
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Lavado-Autric R, Auso E, Garcia-Velasco JV, Arufe Mdel C, Escobar del Rey F, Berbel P, Morreale de Escobar G. (2003). Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clin Invest 111:1073-1082.
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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.
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Wheeler SM, McAndrews MP, Sheard ED, Rovet J. (2012). Visuospatial associative memory and hippocampal functioning in congenital hypothyroidism. J Int Neuropsychol Soc 18:49-56.
Wheeler SM, McLelland VC, Sheard E, McAndrews MP, Rovet JF. (2015). Hippocampal Functioning and Verbal Associative Memory in Adolescents with Congenital Hypothyroidism. Front Endocrinol (Lausanne) 6:163.
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