API

Relationship: 1506

Title

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TH synthesis, Decreased leads to Impairment, Learning and memory

Upstream event

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TH synthesis, Decreased

Downstream event

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Impairment, Learning and memory

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment non-adjacent High Moderate

Taxonomic Applicability

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Term Scientific Term Evidence Link
rat Rattus norvegicus Moderate NCBI
human Homo sapiens Moderate NCBI

Sex Applicability

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Sex Evidence
Unspecific Moderate

Life Stage Applicability

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Term Evidence
During brain development High

Key Event Relationship Description

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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

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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.

Biological Plausibility

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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).

Empirical Evidence

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A number of studies have consistently reported alterations in synaptic transmission resulting from developmental TH disruption, and leading to decreased cognition. Developmental hypothyroidism reduces the functional integrity in brain regions critical for learning and memory. For example, pyramidal neurons of hypothyroid animals have fewer synapses and an impoverished dendritic arbor (Rami et al., 1986a, Madeira et al., 1992) that would lead to cognitive impairments.

Both hippocampal regions (area CA1 and dentate gyrus) exhibit alterations in excitatory and inhibitory synaptic transmission following reductions in serum TH in the pre and early postnatal period (Vara et al., 2002; Sui and Gilbert, 2003; Sui et al., 2005; Gilbert and Sui, 2006; Taylor et al., 2008; Gilbert, 2011; Gilbert et al., 2016). These deficits persist into adulthood long after recovery to euthyroid status.

Hypothyroidism, induced by different approaches, including inhibition of TH synthesis, during development reduces the capacity for synaptic plasticity in juvenile and adult offspring (Vara et al., 2002; Sui and Gilbert, 2003; Dong et al., 2005; Sui et al., 2005; Gilbert and Sui, 2006; Taylor et al., 2008; Gilbert, 2011; Gilbert et al., 2016). Impairments in synaptic function and plasticity are observed coincident with deficits in learning tasks that require the hippocampus.

Several in vivo studies have reported associations between decrease of TH synthesis (induced by TPO inhibitors) and learning and memory impairments:

- Davenport and Dorcey, 1972; Tamasy et al., 1986: In these in vivo studies, deficits in passive avoidance learning have been reported, but these early observations are often limited to animals suffering fairly severe hormonal deprivation.

- Akaike, 1991: in this in vivo study, temporary hypothyroidism was induced in neonatal rats by 0.02% PTU administration to lactating dams during days 0-19 after delivery.  The radial arm maze test started at 13 weeks revealed that the PTU animals required more trials until they showed the first well-performed trial (with 3-fold more errors on day 3). The total number of choices was also larger, with less correct choices. These results suggest an involvement of temporary neonatal hypothyroidism in learning and memory impairment.

- Axelstad et al., 2008: in this in vivo study, radial arm maze deficits were recorded in adult offspring of rat dams treated with high doses of the TPO inhibitor, propylthiouracil (PTU), throughout gestation and lactation. Data showed a ~66% increase in the total number of errors made in the radial arm maze during 3 weeks of testing, in adult male rats perinatally exposed to 1.6 mg/kg/day of PTU from GD7 to PND17.

- Shafiee et al., 2016: This in vivo study investigated the effects of PTU (TPO inhibitor, 100 mg/L) in pregnant rats to evaluate the effects elicited by maternal hypothyroidism in the offspring. PTU was added to the drinking water from gestation day 6 to PND 21. Analysis of hippocampal BDNF levels, and learning and memory tests were performed on PNDs 45-52 on pups. These results indicated that hypothyroidism during the fetal period and the early postnatal period was associated with: (i) ~ 70% reduction of total serum T4, (ii) ~ 5-fold increase of total serum TSH levels (on PND 21; no significant differences could be found at the end of the behavioral testing, on PND 52), (iii) reduction of hippocampal BDNF protein levels (~ 8% decrease vs control), (iv) impairment of spatial learning and memory, in both male and female rat offspring.

- Gilbert et al., 2016: in this in vivo study, exposure to PTU during development produced dose-dependent reductions in mRNA expression of nerve growth factor (Ngf) in whole hippocampus of neonates. These changes in basal expression persisted to adulthood despite the return to euthyroid conditions in blood. Developmental PTU treatment dramatically reduced the activity-dependent expression of neurotrophins and related genes in neonate hippocampus and was accompanied by deficits in hippocampal-based learning (e.g., mean latency to find a hidden platform, at 2nd trial resulted ~60% higher in rats treated with 10 ppm PTU).

- Gilbert and Sui, 2006: in this in vivo study, administration of 3 or 10 ppm PTU to pregnant and lactating dams via the drinking water from GD6 until PND30 caused a 47% and 65% reduction in serum T4, in the dams of the low and high-dose groups, respectively. Baseline synaptic transmission was impaired in PTU-exposed animals: mean EPSP slope (by ~60% with 10 ppm PTU) and population spike amplitudes (by ~70% with 10 ppm PTU) in the dentate gyrus were reduced in a dose-dependent manner in adult offspring of PTU-treated dams. High-dose animals (10 ppm) demonstrated very little evidence of learning despite 16 consecutive days of training (~5-fold higher mean latency to find the hidden platform, used as an index of learning).

- Gilbert, 2011: in this in vivo study, trace fear conditioning deficits to context and to cue were reported in animals treated with PTU; animals also displayed synaptic transmission and LTP deficits in hippocampus. Baseline synaptic transmission was impaired in PTU-exposed animals (by ~50% in animal treated with 3 ppm PTU). EPSP slope amplitudes in the dentate gyrus were reduced in a dose-dependent manner in adult offspring of PTU-treated dams.

 

In addition, studies in humans have shown associations between hypothyroidism and decreased memory and learning:

- Oerbeck et al., 2003: This study reported visual and verbal memory deficits in congenitally hypothyroid (CH) children. The CH group attained significantly lower scores than control subjects on intellectual, motor, and school-associated tests (total IQ: 102.4 vs 111.4). All verbal memory tasks were impaired; visual memory domain gave less consistent findings.

- Wheeler et al., 2011: Functional magnetic resonance imaging (fMRI) data from humans support the relationship between decreased serum concentrations of TH (occurring as a consequence of a decrease of TH synthesis) and memory deficits. CH subjects scored significantly below controls on indices of verbal but not visual memory as well as aspects of everyday memory functioning.

- Willoughby et al., 2013: The present study analysed 26 children with early-treated congenital hypothyroidism (CH), 23 children born to women with inadequately treated hypothyroidism during pregnancy (HYPO), and 30 typically developing controls. Results showed that relative to controls, CH and HYPO groups both exhibited weaknesses in episodic autobiographical memory, but not semantic autobiographical memory. In particular, CH and HYPO groups showed difficulty in recalling event details (i.e., the main happenings) and visual details from past experiences, confirming memory deficits.

- Willoughby et al., 2014: Congenitally hypothyroid children and children born to women with high TSH during pregnancy (biomarker of decreased TH synthesis) were weaker in recalling event and perceptual details from past naturally-occurring autobiographical events than age matched controls. HYPO cases scored significantly below controls on one objective and several subjective memory indices, and these were correlated with lower hippocampal volumes (brain region critical for learning and memory).

Uncertainties and Inconsistencies

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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.

Quantitative Understanding of the Linkage

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Temporal concordance between decrease of TH synthesis and disrupted brain development leading to learning and memory impairment has repeatedly been documented by demonstrating that there are critical windows during brain development where permanent changes are triggered. Hormone replacement studies have also demonstrated that structural alterations in brain are reduced or eliminated if T4 (and/or T3) treatment is given during critical developmental windows (Goodman and Gilbert., 2007; Auso et al., 2004; Lavado-Autric et al., 2003; Berbel et al., 2010; Koibuchi and Chin, 2000). However, quantitative data in support of this indirect KER are not available.

Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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Deficiencies in learning and memory following developmental hypothyroidism (TH synthesis inhibition) have been documented mainly in rodents and humans.

References

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Akaike M, Kato, N., Ohno, H., Kobayashi, T. (1991). Hyperactivity and spatial maze learning impairment of adult rats with temporary neonatal hypothyroidism. Neurotoxicol Teratol 13:317-322.

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.

Axelstad M, Hansen PR, Boberg J, Bonnichsen M, Nellemann C, Lund SP, Hougaard KS, U H. (2008). Developmental neurotoxicity of Propylthiouracil (PTU) in rats: relationship between transient hypothyroxinemia during development and long-lasting behavioural and functional changes. Toxicol Appl Pharmacol 232:1-13.

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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