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TH synthesis, Decreased leads to BDNF, Reduced
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||Low||Low||Anna Price (send email)||Open for citation & comment||WPHA/WNT Endorsed|
Life Stage Applicability
|During brain development||Moderate|
Key Event Relationship Description
Several studies have shown that THs regulate BDNF expression in the brain (Koibuchi et al., 1999; Koibuchi and Chin, 2000; Sui and Li, 2010), with the subsequent neurodevelopmental consequences, as described in the direct KER. For example, during the early cortical network development TH has been shown to regulate the morphology and function of the GABAergic neurons (Westerholz et al., 2010) and BDNF is one of the mediators of this regulation (Binder and Scharfman, 2004; Gilbert and Lasley, 2013).
In view of the above evidence, it has been suggested that the thyroid insufficiency triggered by inhibition of TPO or NIS functions, resulting in decreased TH synthesis and subsequent lowered TH levels in serum and brain, may lead to reduction of the levels of BDNF mRNA or protein in the developmental brain.
Evidence Supporting this KER
The importance of 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, even in the modest degree, 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). The levels of serum TH at birth are not always informative, as most of the neurological deficits are present despite the normal thyroid status of the newborn. That means that the cause of these impairments is rooted in the early stages of the neuronal development during the gestational period. The nature and the temporal occurrence of these defects suggest that TH may exert their effects through the neurotrophins, as they are the main regulators of neuronal system development (Lu and Figurov, 1997). Among them, BDNF represents the prime candidate because of its critical role in CNS development and its ability to regulate synaptic transmission, dendritic structure and synaptic plasticity in adulthood (Binder and Scharfman, 2004). Additionally, hippocampus and neocortex are two of the regions characterized by the highest BDNF expression (Kawamoto et al., 1996), and are also key brain areas for learning and memory functions.
Uncertainties and Inconsistencies
Despite the fact that many in vivo studies have shown a correlation between hypothyroidism and decreased BDNF expression in the brain, no clear consensus can be reached by the overall evaluation of the existing data. There are numerous conflicting studies showing no significant alterations in BDNF mRNA or protein levels (Alvarez-Dolado et al., 1994; Bastian et al., 2010; 2012; Royland et al., 2008; Lasley and Gilbert, 2011). However, the results of these studies cannot exclude the possibility of temporal- or region-specific BDNF effects as a consequence of foetal hypothyroidism. A transient TH-dependent BDNF reduction in early postnatal life can be followed by a period of normal BDNF levels or, on the contrary, normal BDNF expression in the early developmental stages is not predictive of equally normal BDNF expression throughout development. Moreover, significant differences in study design, the assessed brain regions, the age and the method of assessment in the existing studies, further complicate result interpretation.
While PTU (TPO inhibitor) has been shown to decrease brain BDNF levels and expression in offspring born from PTU-treated rat dams (Shafiee et al. 2016; Chakraborty et al., 2012; Gilbert et al. 2016), in Cortés et al., 2012 study (in vivo), treatment of adult male Sprague-Dawley rats with PTU induced an increase in the amount of BDNF mRNA in the hippocampus, while the content of TrkB, the receptor for BDNF, resulted reduced at the postsynaptic density (PSD) of the CA3 region compared with controls. Treated rats presented also thinner PSD than control rats, and a reduced content of NMDAr subunits (NR1 and NR2A/B subunits) at the PSD in hypothyroid animals. These indicate differential effects elicited by PTU (i.e., TPO inhibition) on BDNF expression/regulation comparing the adult vs foetal brain. However, even though BDNF levels were increased, the decrease of BDNF receptor (TrkB) compromises the signalling pathway under BDNF control.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The connection between synthesis of TH and BDNF expression has been studied only in rodent models up to date.
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