Relationship: 384



Altered, Neurophysiology leads to Cognitive Function, Decreased

Upstream event


Altered, Neurophysiology

Downstream event


Cognitive Function, Decreased

Key Event Relationship Overview


AOPs Referencing Relationship


AOP Name Directness Weight of Evidence Quantitative Understanding
XX Inhibition of Sodium Iodide Symporter and Subsequent Adverse Neurodevelopmental Outcomes in Mammals directly leads to Moderate Weak

Taxonomic Applicability


Sex Applicability


Life Stage Applicability


How Does This Key Event Relationship Work


Cognitive function and impairments thereof are measured using behavioral techniques. It is well accepted that these alterations in behavior are the result of structural or functional changes in neurocircuitry. Functional impairments are often measured using field potentials of critical synaptic circuits in hippocampus and cortex. A number of studies have been performed in rodent models that reveal deficits in both excitatory and inhibitory synaptic transmission in the hippocampus as a result of developmental thyroid insufficiency.

A well established model of memory at the synaptic levels is known as long-term potentiation (LTP). Deficiencies in LTP are generally regarded as potential substrates of learning and memory impairments.

Weight of Evidence


A number of studies have consistently reported alterations in synaptic transmission resulting from developmental TH disruption and impairments in behavioral tasks assessing learning and memory. It is not clear if all behavioral impairments reported can be directly tied to synaptic dysfunction in the brain regions within which neurotransmission deficits have been recorded. It is not unreasonable to posit that the mechanisms of supporting synaptic transmission and synaptic strengthening are similar in different regions of the brain that support learning and memory and that demonstration at one site where it is most readily assessed implicates this mechanism may also be impaired at other sites as well.

Biological Plausibility


It is well accepted that alterations in synaptic transmission and plasticity contribute to deficits in cognitive function. There are a few studies that have linked exposure to TPO inhibitors (e.g., PTU, MMI) and well as iodine deficient diets, to changes in serum TH levels and have measured both alterations in both synaptic function and cognitive behaviors (Opazo et al., 2009; Dong et al., 2005; Gilbert, 2011; Gilbert and Sui, 2006).

Empirical Support for Linkage


Developmental hypothyroidism reduces the functional integrity in brain regions critical for learning and memory. Neurophysiological indices of synaptic transmission of excitatory and inhibitory circuitry are impaired in hypothyroid animals. Two regions of the hippocampus, area CA1 and the dentate gyrus, have received the most study due to their ease of assess and the robustness of the recorded responses in ex vivo and in vivo preparations. Both regions exhibit alterations in excitatory and inhibitory synaptic transmission following reductions in serum TH in the pre and early postnatal period (Dong et al., 2005; Gilbert, 2011; Gilbert and Sui, 2006; Sui and Gilbert, 2003; Taylor et al., 2008; Vara et al, 2002). These deficits persist into adulthood long after recovery to euthyroid status (Gilbert and Sui; 2006; Gilbert, 2011). The latter observation indicates that these alterations represent permanent changes in brain function induced from transient hormones insufficiencies induced during critical window of development.

Because the adult hippocampus is involved in learning and memory, it is a brain region of remarkable plasticity. Use-dependent synaptic plasticity is critical during brain development for synaptogenesis and fine tuning of synaptic connectivity. In the adult brain, similar plasticity mechanisms underlie use-dependency that underlies learning and memory as exhibited in long-term potentiation (LTP) model of synaptic memory. Hypothyroidism during development reduces the capacity for synaptic plasticity in juvenile and adult offspring (Taylor et al., 2008; Sui and Gilbert, 2003; Gilbert and Sui, 2006; Gilbert, 2011; Dong et al., 2005).

In animal models of developmental hypothyroidism, deficits in passive avoidance learning, spatial learning, and operant conditioning (Davenport and Dorcey 1972; Schalock et al. 1979; Tamasy et al. 1986; Akaike et al. 1991; Brosvic et al, 2002), have been reported, but these early observations are often limited to animals suffering fairly severe hormonal deprivation. At these levels of hormone deprivation, clear evidence of synaptic dysfunction and impaired plasticity has been reported (Dong et al., 2005; Vara et al., 2002; Gilbert and Pazckowski, 2003). More recent data have demonstrated persistent impairments in a variety of learning tasks with more modest reductions in serum TH induced by TPO inhibitors (Axelstad et al., 2009; Darbra et al., 2003; 2004; Gilbert and Sui, 2006; Gilbert, 2011). Subtle impairments accompanying moderate levels of hormone insufficiency require more sensitive behavioral assessments and have been observed coincident with synaptic transmission and plasticity deficits (Gilbert, 2011).

Temporal concordance of TH insufficiency and disrupted development, defined at many levels of biological organization. There are critical windows during development where permanent changes are affected. Hormone replacement studies have demonstrated that structural alterations in brain are reduced or eliminated if T4 (and/or T3) treatment is given during the critical windows (Goodman and Gilbert, 2008; Auso et al., 2004; Lavado-Autric et al., 2003; Berbel et al., 2010; Koibuchi and Chin, 2000). Induction of graded degrees of TH insufficiency in dams and pups by administering varying doses of TPO inhibitors have demonstrated, in the absence of overt signs of toxicity in dams or the pups, dose-dependent alterations in synaptic transmission, synaptic plasticity, and performance on a variety of learning and memory tasks (Gilbert and Sui, 2006; Gilbert, 2011; Dong et al., 2005; Gilbert et al., 2013; Sui and Gilbert, 2003; Taylor et al., 2008).

Uncertainties or Inconsistencies


The direct relationship of alterations in synaptic function and specific cognitive deficits is difficult to ascertain given the many forms that learning and memory can take and the complexity of synaptic interactions in even the simplest brain circuit. Linking of neurophysiological assessments to learning and memory processes have, by necessity, been made across simple monosynaptic connections and largely focused on the hippocampus. Alterations in synaptic function, however, have been found in the absence of behavioral impairments (e.g., Gilbert et al., 2013; 2007). This may result from: 1) Measuring only one component in the complex brain circuitry that underlies 'cognition' 2) Behavioral tests typically used in large dose-response studies allow for processing of large numbers of animals and may not be sufficiently sensitive to detect subtle cognitive impairments 3) Behavioral tasks may be solved by a number of differnt strategies - animals develop alernative strategies as a consequence of developmental insult to compensate for impaired ability.

Quantitative Understanding of the Linkage


There is very limited information on the degree of change in synaptic activity required to alter cognitive behaviors. This is a result of the diversity of methods for measuring both physiology and cognitive function, that hamper cross-study analyses.

This highlights the need to develop empirical data based models of this key relationship.

Evidence Supporting Taxonomic Applicability


Synaptic transmission and plasticity are acheived via mechanisms common across taxonomies. LTP has been recorded in aplysia, lizards, turtles, birds, mice, guinea pigs, rabbits and rats.



These references need to be checked. Section on acute effects T3 on LTP and PPF in adult also needs to be added to text above.

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