Brain regional thyroid hormone status and Dio3: where genetics, epigenetics and psychiatric vulnerability meet

Keywords::

• genetic imprinting
• iodothyronine deiodinase type III
• psychiatric disease
• triiodothyronine

Thyroid hormones (TH), thyroxine (T4) and triiodothyronine (T3), are critical for metabolic homeostasis as well as brain development and functioning. The bioactive T3, metabolized from T4, binds to a family of nuclear thyroid hormone receptors (TR) and thereby regulates the transcription of neurodevelopmental genes. Expression of the α and β TR subfamilies in the brain is isoform and region specific [1]. Deletion of a specific receptor subtype highly prevalent in the brain has been shown to lead to region-specific changes in hippocampal circuitry that correlate to behavioral deficits [2]. Similarly, developmental TH imbalances do not have uniform consequences throughout the brain, but rather, they manifest in clusters of cognitive, affective and behavioral deficits [3–5]. This suggests a regionalization of differing TH sensitivity within the developing brain. What is not well known is whether, and how, TH levels themselves might be regionally regulated within a network of brain regions, and furthermore, how such regionalization could affect mood, cognition or social behavior not only in development, but also in the adult.

Neuronal deiodinase type III gates T3 from the nucleus

Thyroid hormones in the brain are made available from the periphery via a group of TH transporters that include MCT8, TTR, OATP14, Lat1, Lat2 and others. The organic ion transporter-14 (OATP14) is thought to transport T4 across the blood–brain barrier where it is metabolized to T3 in astrocytes, which express the deiodinase type II (Dio2) enzyme. This locally produced T3 is then delivered to neurons by a compliment of transporters, including the neuronal membrane transporter monocarboxylate transporter-8 (MCT8) [6–10]. Once T3 has entered the neuron, its availability is ultimately determined by the presence or absence of the T3-inactivating enzyme, deiodinase type III (Dio3). Dio3 is an integral membrane protein, which, in the brain, is found in neurons. Its catalytic domain is thought to be inside the plasma membrane, where it catalyzes the inner ring deiodination of T3, rendering it inactive before it reaches the nucleus [11,12]. The lack of Dio3 leads to septal and cortical brain thyrotoxicosis at postnatal day 5 and again throughout the adult brain, despite reduced levels of THs in the periphery [13]. Recently, further work has shown that localized increases or decreases of Dio3 protein levels, due to prenatal T4 supplementation or to genetic causes, in brain regions such as amygdala and hippocampus affect the thyroid status of the individual brain region [14,15]. These data highlight that Dio3 regulates T3 levels at a highly local level in the brain, not only during development, but also in adulthood.

Genetic & epigenetic regulation of Dio3 & malleability by the environment

Located at the distal portion of the imprinted Dlk1–Dio3 cluster, Dio3 exhibits incomplete silencing of the maternal allele and preferential paternal expression in murine embryonic tissues as well as rat fetal brain regions [15–19]. Dio3 expression subsequently relaxes to biallelic expression in the adult rat brain and in the adult mouse cortex [15,19,20]. Preferential parent-of-origin expression rather than complete silencing of one allele, although uncommon among imprinted genes, has been seen previously in mice [21]. The fact that Dio3 is subject to epigenetic regulation opens the possibility that Dio3 integrates genetic and early environmental influences on thyroid-regulated brain functions.

Genetic variation in imprinted loci often results in deficits that are neurodevelopmental in nature. Examples that have been characterized include Prader–Willi and Angelman syndromes [22]. Recently, a more moderate neurobehavioral phenotype of increased anxiety-related behavior and memory impairment was found strain-specifically in rats that endogenously exhibit altered parent-of-origin expression of Dio3[15]. The allelic expression ratio of Dio3 was preferentially maternal in the hippocampus of one hybrid rat cross but not in the other reciprocal cross, which exhibited normal expression. In the affected cross, the alteration in the Dio3 imprinting status corresponded to decreased paternal and total mRNA levels of Dio3 in fetal and adult hippocampus, as well as increased hippocampal T3 levels in the adult. None of these findings were seen in the frontal cortex, where Dio3 exhibited the expected paternal and subsequently biallelic expression in both reciprocal crosses. Taken together, these findings raise the possibility that parent-of-origin-specific genetic variation in Dio3 or its regulators could also have functional consequences on localized thyroid hormone levels within the brain in humans. Thus, brain regional misregulation of Dio3 levels, and thereby increased or decreased T3 availability, is likely an important etiological component of various neurodevelopmental and neuropsychiatric disorders.

Regional T3 availability can be affected not only by genetics but also by the environment. Prenatal exposure to alcohol consumed by the mother disrupted parent-of-origin-specific Dio3 expression with consequences on enzyme expression, regional T3 levels in the hippocampus, and social and memory deficits [19]. Those hybrid rats showing maternal hippocampal Dio3 expression manifested even less paternal contribution and further decreased Dio3 transcript levels in the hippocampus when they were prenatally exposed to alcohol. They also had higher hippocampal T3 levels than adults and impaired social and memory performance compared with controls. However, the genetically identical animals of the reciprocal hybrid strain did not demonstrate effects of prenatal alcohol exposure on Dio3 imprinting, Dio3 levels or T3 levels in the adult brain regions, presumably owing to stable biallelic levels of Dio3 expression in the fetal and adult hippocampus. These data illustrate the potential for imprinted Dio3 expression to be adversely affected by other prenatal insults in addition to alcohol exposure, such as food restriction, stress or drugs. Until now, behavioral phenotypes have not been included in the exploration of how parent-of-origin-specific expression combined with polymorphisms shapes disease states [23], but the described study comprises one of the first efforts toward a deeper understanding of complex behaviors.

Thyroid hormone-related psychopathology: Dio3 genotype-dependent brain thyroid metabolism?

The longstanding relationship between thyroid abnormalities and psychiatric symptoms in humans [24,25] and behavioral deficits in animals [4,26,27] supports the idea that THs affect susceptibility to specific psychiatric conditions. TH supplementation has been used as an augmentation strategy in treatment-resistant depression and has resulted in clinical improvement greater than placebo in a meta-analysis, averaging an approximate 50–60% response rate [28,29]. It is suggested that treatment-resistant patients benefit from TH treatment because the brain is hypothyroid, even when the periphery is euthyroid. Indeed, we propose that genetic differences in brain region-specific regulators of TH availability probably explain differences in psychiatric vulnerability, and ultimately, why some individuals benefit from TH augmentation treatment while others do not. For example, recent findings show that in major depressive disorder single-nucleotide polymorphisms in TH transporters are correlated with gray matter volume in specific regions of the brain, a known correlate of the disorder [30]. Evidence obtained from animals indicates directly that genetic background can impact on hippocampal-specific Dio3 regulation, T3 levels and behavior [15]. Furthermore, region-specific expression of TH transporters and the deiodinases suggests that peripheral TH imbalances could affect specific brain regions differently and that different brain regions have different TH needs [31,32]. Cortical and hippocampal regions are perhaps particularly vulnerable to changes in peripheral or local TH status [15,19,33,34] as they exhibit the highest levels of transporters found anywhere in the brain, highly express Dio2 and Dio3, and are key in the etiology of mental illness.

Further work is needed to show associations between brain region-specific thyroid status and aspects of psychiatric disease in humans. In addition, studies will show how the environment interacts with the genetic factors to determine a spectrum of TH-related psychiatric phenotypes and responses to TH treatments. We suggest that environmental–genetic influences on Dio3 expression affect psychiatric vulnerability through their ability to change the TH availability in discrete brain regions. This expanding picture will provide many new opportunities by uniting the thyroid literature with neuroscience in the current light of epigenetic research.

Financial & competing interests disclosure

NIH grants R01AA017978 and R01AA013452 have been awarded to Eva E Redei, and grant F31AA018251 to Laura J Sittig. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.