Table 1.

Experimental studies demonstrating brain areas affected by maternal hypothyroxinemia.

	Study Design	Structural Alterations	Functional or Clinical Consequences
Lavado-Autric (2003) [21]	Rat dams fed a low iodine diet	Significant proportion of neurons found at locations that were aberrant or inappropriate with respect to birth date	Alteration in foetal brain histogenesis and cytoarchitecture might explain cognitive impairment in the progeny
Ausó (2004) [22]	Inducement of mild and transient hypothyroxinemia in rat dams by methimazole (MMI)	The cytoarchitecture and the radial distribution of neurons was significantly affected in the somatosensory cortex and hippocampus	Increased frequency of abnormal responses to acoustic stimulus Susceptibility to audiogenic seizures
Opazo (2008) [23]	Inducement of maternal hypothyroxinemia in rat dams by MMI	A significant reduction in the capacity of the brain for spatial learning Impaired dendrite and synapse stability Detrimental changes in long-term potentiation, affecting cognitive processes	Impaired learning capacity, prolonged latency of learning process
Babu (2011) [24]	Rat dams were fed a low iodine diet and given 1% KClO4 in drinking water (to lower the iodine content in the thyroid gland)	Significant decrease in myelin basic protein (MBP) and mitochondrial gene for cytochrome c oxidase III (Cox III) levels during neocortical development Increased number of apoptotic neurons distributed in all the layers of the neocortex	Thyroid hormone responsiveness in postnatal cortex is more sensitive to decrease in T4 than T3 concentration
Pinazo-Durán (2011) [25]	A rat model of controlled thyroid hormone deficiency	Delayed glial development and myelination in optic nerve	Reduction in the volume of the eye and optic nerve cross-sectional area Thinning of the retinal layers
Wei (2013) [26]	Four groups of rat dams: control group, mild ID, severe ID and MMI-treatment group	Impaired growth of axonal-related proteins Delayed axonal growth in hippocampus Damage of the morphological axon in the developing hippocampus	The deficits in axonal development might promote axonal regeneration in the hippocampus, but this process might not fully compensate for the damage induced by low thyroxine.
Gilbert (2014) [27]	Rat dams were exposed to propylthiouracil (PTU) in their drinking water to inhibit the thyroid hormone synthesis	Presence of subcortical-band heterotopia (SBH), a type of neuronal migration error resulting in neurones, oligodendrocytes and microglia in the corpus callosum of the offspring.	SBH in humans is an important type of malformation often associated with intractable epilepsy of childhood.
Wang (2014) [28]	A maternal hypothyroxinemia model (using mild ID diet) and two maternal hypothyroidism models (through a severe ID diet and MMI water respectively)	Reduced proliferation of cerebellar granule neuron precursors (CGNPs) Decreased total dendritic length of Purkinje cells (the most important neurons in the cerebellum)	Affected motor coordination and motor activity in which the cerebellum plays a critical role.
Cisternas (2016) [29]	Inducement of maternal hypothyroxinemia in rat dams by MMI	Affected synaptic protein distribution and impaired neuronal function. This deleterious effect is dependent on astrocyte and neuron integrity.	Affected neuronal plasticity which is dependent on interplay between astrocytes and neurons.
Gilbert (2016) [30]	Rat dams were exposed to propylthiouracil (PTU) in their drinking water to inhibit thyroid hormone synthesis	Reduced expression of neurotrophins that are important for neural processing. Restricted activity-dependent induction of neuroplasticity in the hippocampus. Changes persisted into adulthood despite the return to euthyroidism.	Altered structural and functional pathways in both the developing and adult brain.
Opazo (2017) [31]	Inducement of maternal hypothyroxinemia in rat dams by MMI	Unbalanced reactivity of microglia (decreased) and astrocytes (increased) to inflammatory stimuli.	Astrocytes could react strongly in inflammation, inducing neuronal death in the central nervous system.