Thyroid hormone action in adult neurogliogenic niches: the known and unknown.

Over the last decades, thyroid hormones (THs) signaling has been established as a key signaling cue for the proper maintenance of brain functions in adult mammals, including humans. One of the most fascinating roles of THs in the mature mammalian brain is their ability to regulate adult neurogliogenic processes. In this respect, THs control the generation of new neuronal and glial progenitors from neural stem cells (NSCs) as well as their final differentiation and maturation programs. In this review, we summarize current knowledge on the cellular organization of adult rodent neurogliogenic niches encompassing well-established niches in the subventricular zone (SVZ) lining the lateral ventricles, the hippocampal subgranular zone (SGZ), and the hypothalamus, but also less characterized niches in the striatum and the cerebral cortex. We then discuss critical questions regarding how THs availability is regulated in the respective niches in rodents and larger mammals as well as how modulating THs availability in those niches interferes with lineage decision and progression at the molecular, cellular, and functional levels. Based on those alterations, we explore the novel therapeutic avenues aiming at harnessing THs regulatory influences on neurogliogenic output to stimulate repair processes by influencing the generation of either new neurons (i.e. Alzheimer's, Parkinson's diseases), oligodendrocytes (multiple sclerosis) or both (stroke). Finally, we point out future challenges, which will shape research in this exciting field in the upcoming years.

The Differential Effect of a Shortage of Thyroid Hormone Compared with Knockout of Thyroid Hormone Transporters Mct8 and Mct10 on Murine Macrophage Polarization.

Innate immune cells, including macrophages, are functionally affected by thyroid hormone (TH). Macrophages can undergo phenotypical alterations, shifting between proinflammatory (M1) and immunomodulatory (M2) profiles. Cellular TH concentrations are, among others, determined by TH transporters. To study the effect of TH and TH transporters on macrophage polarization, specific proinflammatory and immunomodulatory markers were analyzed in bone marrow-derived macrophages (BMDMs) depleted of triiodothyronine (T3) and BMDMs with a knockout (KO) of Mct8 and Mct10 and a double KO (dKO) of Mct10/Mct8. Our findings show that T3 is important for M1 polarization, while a lack of T3 stimulates M2 polarization. Mct8 KO BMDMs are unaffected in their T3 responsiveness, but exhibit slight alterations in M2 polarization, while Mct10 KO BMDMs show reduced T3 responsiveness, but unaltered polarization markers. KO of both the Mct8 and Mct10 transporters decreased T3 availability and, contrary to the T3-depleted BMDMs, showed partially increased M1 markers and unaltered M2 markers. These data suggest a role for TH transporters besides transport of TH in BMDMs. This study highlights the complex role of TH transporters in macrophages and provides a new angle on the interaction between the endocrine and immune systems.

Proteome Analysis of Thyroid Hormone Transporter Mct8/Oatp1c1-Deficient Mice Reveals Novel Dysregulated Target Molecules Involved in Locomotor Function.

Thyroid hormone (TH) transporter MCT8 deficiency causes severe locomotor disabilities likely due to insufficient TH transport across brain barriers and, consequently, compromised neural TH action. As an established animal model for this disease, Mct8/Oatp1c1 double knockout (DKO) mice exhibit strong central TH deprivation, locomotor impairments and similar histo-morphological features as seen in MCT8 patients. The pathways that cause these neuro-motor symptoms are poorly understood. In this paper, we performed proteome analysis of brain sections comprising cortical and striatal areas of 21-day-old WT and DKO mice. We detected over 2900 proteins by liquid chromatography mass spectrometry, 67 of which were significantly different between the genotypes. The comparison of the proteomic and published RNA-sequencing data showed a significant overlap between alterations in both datasets. In line with previous observations, DKO animals exhibited decreased myelin-associated protein expression and altered protein levels of well-established neuronal TH-regulated targets. As one intriguing new candidate, we unraveled and confirmed the reduced protein and mRNA expression of Pde10a, a striatal enzyme critically involved in dopamine receptor signaling, in DKO mice. As altered PDE10A activities are linked to dystonia, reduced basal ganglia PDE10A expression may represent a key pathogenic pathway underlying human MCT8 deficiency.

Local Thyroid Hormone Action in Brain Development.

Proper brain development essentially depends on the timed availability of sufficient amounts of thyroid hormone (TH). This, in turn, necessitates a tightly regulated expression of TH signaling components such as TH transporters, deiodinases, and TH receptors in a brain region- and cell-specific manner from early developmental stages onwards. Abnormal TH levels during critical stages, as well as mutations in TH signaling components that alter the global and/or local thyroidal state, result in detrimental consequences for brain development and neurological functions that involve alterations in central neurotransmitter systems. Thus, the question as to how TH signaling is implicated in the development and maturation of different neurotransmitter and neuromodulator systems has gained increasing attention. In this review, we first summarize the current knowledge on the regulation of TH signaling components during brain development. We then present recent advances in our understanding on how altered TH signaling compromises the development of cortical glutamatergic neurons, inhibitory GABAergic interneurons, cholinergic and dopaminergic neurons. Thereby, we highlight novel mechanistic insights and point out open questions in this evolving research field.

Thyroid hormone transporter Mct8/Oatp1c1 deficiency compromises proper oligodendrocyte maturation in the mouse CNS.

Proper CNS myelination depends on the timed availability of thyroid hormone (TH) that induces differentiation of oligodendrocyte precursor cells (OPCs) to mature, myelinating oligodendrocytes. Abnormal myelination is frequently observed in Allan-Herndon-Dudley syndrome caused by inactivating mutations in the TH transporter MCT8. Likewise, persistent hypomyelination is a key CNS feature of the Mct8/Oatp1c1 double knockout (Dko) mouse model, a well-established mouse model for human MCT8 deficiency that exhibits diminished TH transport across brain barriers and thus a TH deficient CNS. Here, we explored whether decreased myelin content is caused by an impairment in oligodendrocyte maturation. To that end, we studied OPC and oligodendrocyte populations in Dko mice versus wild-type and single TH transporter knockout animals at different developmental time points (at postnatal days P12, P30, and P120) using multi-marker immunostaining and confocal microscopy. Only in Dko mice we observed a reduction in cells expressing the oligodendroglia marker Olig2, encompassing all stages between OPCs and mature oligodendrocytes. Moreover, Dko mice exhibited at all analysed time points an increased portion of OPCs and a reduced number of mature oligodendrocytes both in white and grey matter regions indicating a differentiation blockage in the absence of Mct8/Oatp1c1. We also assessed cortical oligodendrocyte structural parameters by visualizing and counting the number of mature myelin sheaths formed per oligodendrocyte. Again, only Dko mice displayed a reduced number of myelin sheaths that in turn exhibited an increase in length indicating a compensatory response to the reduced number of mature oligodendrocytes. Altogether, our studies underscore an oligodendrocyte differentiation impairment and altered oligodendrocyte structural parameters in the global absence of Mct8 and Oatp1c1. Both mechanisms most likely do not only cause the abnormal myelination state but also contribute to compromised neuronal functionality in Mct8/Oatp1c1 deficient animals.

Triac Treatment Prevents Neurodevelopmental and Locomotor Impairments in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice.

Patients with inactive thyroid hormone (TH) transporter MCT8 display intellectual disability due to compromised central TH transport and action. As a therapeutic strategy, application of thyromimetic, MCT8-independent compounds Triac (3,5,3'-triiodothyroacetic acid), and Ditpa (3,5-diiodo-thyropropionic acid) was proposed. Here, we directly compared their thyromimetic potential in Mct8/Oatp1c1 double knock-out mice (Dko) modeling human MCT8 deficiency. Dko mice received either Triac (50 ng/g or 400 ng/g) or Ditpa (400 ng/g or 4000 ng/g) daily during the first three postnatal weeks. Saline-injected Wt and Dko mice served as controls. A second cohort of Dko mice received Triac (400 ng/g) daily between postnatal weeks 3 and 6. Thyromimetic effects were assessed at different postnatal stages by immunofluorescence, ISH, qPCR, electrophysiological recordings, and behavior tests. Triac treatment (400 ng/g) induced normalized myelination, cortical GABAergic interneuron differentiation, electrophysiological parameters, and locomotor performance only when administered during the first three postnatal weeks. Ditpa (4000 ng/g) application to Dko mice during the first three postnatal weeks resulted in normal myelination and cerebellar development but only mildly improved neuronal parameters and locomotor function. Together, Triac is highly-effective and more efficient than Ditpa in promoting CNS maturation and function in Dko mice yet needs to be initiated directly after birth for the most beneficial effects.

TRIAC Treatment Improves Impaired Brain Network Function and White Matter Loss in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice.

Dysfunctions of the thyroid hormone (TH) transporting monocarboxylate transporter MCT8 lead to a complex X-linked syndrome with abnormal serum TH concentrations and prominent neuropsychiatric symptoms (Allan-Herndon-Dudley syndrome, AHDS). The key features of AHDS are replicated in double knockout mice lacking MCT8 and organic anion transporting protein OATP1C1 (Mct8/Oatp1c1 DKO). In this study, we characterize impairments of brain structure and function in Mct8/Oatp1c1 DKO mice using multimodal magnetic resonance imaging (MRI) and assess the potential of the TH analogue 3,3',5-triiodothyroacetic acid (TRIAC) to rescue this phenotype. Structural and functional MRI were performed in 11-weeks-old male Mct8/Oatp1c1 DKO mice (N = 10), wild type controls (N = 7) and Mct8/Oatp1c1 DKO mice (N = 13) that were injected with TRIAC (400 ng/g bw s.c.) daily during the first three postnatal weeks. Grey and white matter volume were broadly reduced in Mct8/Oatp1c1 DKO mice. TRIAC treatment could significantly improve white matter thinning but did not affect grey matter loss. Network-based statistic showed a wide-spread increase of functional connectivity, while graph analysis revealed an impairment of small-worldness and whole-brain segregation in Mct8/Oatp1c1 DKO mice. Both functional deficits could be substantially ameliorated by TRIAC treatment. Our study demonstrates prominent structural and functional brain alterations in Mct8/Oatp1c1 DKO mice that may underlie the psychomotor deficiencies in AHDS. Additionally, we provide preclinical evidence that early-life TRIAC treatment improves white matter loss and brain network dysfunctions associated with TH transporter deficiency.

An animal model for Pierpont syndrome: a mouse bearing the Tbl1xr1Y446C/Y446C mutation.

Pierpont syndrome is a rare disorder characterized mainly by global developmental delay, unusual facial features, altered fat distribution in the limbs and hearing loss. A specific mutation (p.Tyr446Cys) in TBL1XR1, encoding a WD40 repeat-containing protein, which is a component of the SMRT/NCoR (silencing mediator retinoid and thyroid hormone receptors/nuclear receptor corepressors), has been reported as the genetic cause of Pierpont syndrome. Here, we used CRISPR-cas9 technology to generate a mutant mouse with the Y446C mutation in Tbl1xr1, which is also present in Pierpont syndrome. Several aspects of the phenotype were studied in the mutant mice: growth, body composition, hearing, motor behavior, thyroid hormone state and lipid and glucose metabolism. The mutant mice (Tbl1xr1Y446C/Y446C) displayed delayed growth, altered body composition with increased relative lean mass and impaired hearing. Expression of several genes involved in fatty acid metabolism differed in white adipose tissue, but not in liver or muscle of mutant mice compared to wild-type mice (Tbl1xr1+/+). No difference in thyroid hormone plasma concentrations was observed. Tbl1xr1Y446C/Y446C mice can be used as a model for distinct features of Pierpont syndrome, which will enable future studies on the pathogenic mechanisms underlying the various phenotypic characteristics.

Distinct Actions of the Thyroid Hormone Transporters Mct8 and Oatp1c1 in Murine Adult Hippocampal Neurogenesis.

Inactivating mutations in the thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8) result in Allan-Herndon-Dudley Syndrome, a severe form of psychomotor retardation, while inactivating mutations in another TH transporter, organic anion transporting polypeptide 1c1 (OATP1C1), are linked to juvenile neurodegeneration. These diseases point to essential roles for TH transporters in CNS function. We recently defined the presence of Mct8 in adult hippocampal progenitors and mature granule cell neurons and unraveled cell-autonomous and indirect requirements for Mct8 in adult hippocampal neurogenesis. Here, we investigated whether Oatp1c1 is involved in the hippocampal neurogenic process in concert with Mct8. We detected Oatp1c1 gene expression activity and transcripts in subsets of progenitors, neurons and niche cells in the dentate gyrus. Absence of Oatp1c1 resulted in increased neuroblast and reduced immature neuron numbers in 6-month-old Oatp1c1ko and Mct8/Oatp1c1 double knockout (M/Odko) mice. Reduced EdU-label retention in Mct8ko and M/Odko mice confirmed the impact of Mct8 on neuron formation. In contrast, no significant effect of Oatp1c1 loss on granule cell neuron production and anxiety-like behavior in the open field arena were seen. Together, our results reinforce that distinct actions of each TH transporter are required at multiple stages to ensure proper adult hippocampal neurogenesis.

The Thyroid Hormone Transporter MCT10 Is a Novel Regulator of Trabecular Bone Mass and Bone Turnover in Male Mice.

Thyroid hormones (TH) are essential for skeletal development and adult bone homeostasis. Their bioavailability is determined by specific transporter proteins at the cell surface. The TH-specific transporter monocarboxylate transporter 8 (MCT8) was recently reported as a regulator of bone mass in mice. Given that high systemic triiodothyronine (T3) levels in Mct8 knockout (KO) mice are still able to cause trabecular bone loss, alternative TH transporters must substitute for MCT8 function in bone. In this study, we analyzed the skeletal phenotypes of male Oatp1c1 KO and Mct10 KO mice, which are euthyroid, and male Mct8/Oatp1c1 and Mct8/Mct10 double KO mice, which have elevated circulating T3 levels, to unravel the role of TH transport in bone. MicroCT analysis showed no significant trabecular bone changes in Oatp1c1 KO mice at 4 weeks and 16 weeks of age compared with wild-type littermate controls, whereas 16-week-old Mct8/Oatp1c1 double KO animals displayed trabecular bone loss. At 12 weeks, Mct10 KO mice, but not Mct8/Mct10 double KO mice, had decreased trabecular femoral bone volume with reduced osteoblast numbers. By contrast, lack of Mct10 in 24-week-old mice led to trabecular bone gain at the femur with increased osteoblast numbers and decreased osteoclast numbers whereas Mct8/Mct10 double KO did not alter bone mass. Neither Mct10 nor Mct8/Mct10 deletion affected vertebral bone structures at both ages. In vitro, osteoblast differentiation and activity were impaired by Mct10 and Mct8/Mct10-deficiency. These data demonstrate that MCT10, but not OATP1C1, is a site- and age-dependent regulator of bone mass and turnover in male mice.

Thyroid Hormone Transporter Deficiency in Mice Impacts Multiple Stages of GABAergic Interneuron Development.

Cortical interneuron neurogenesis is strictly regulated and depends on the presence of thyroid hormone (TH). In particular, inhibitory interneurons expressing the calcium binding protein Parvalbumin are highly sensitive toward developmental hypothyroidism. Reduced numbers of Parvalbumin-positive interneurons are observed in mice due to the combined absence of the TH transporters Mct8 and Oatp1c1. To unravel if cortical Parvalbumin-positive interneurons depend on cell-autonomous action of Mct8/Oatp1c1, we compared Mct8/Oatp1c1 double knockout (dko) mice to conditional knockouts with abolished TH transporter expression in progenitors of Parvalbumin-positive interneurons. These conditional knockouts exhibited a transient delay in the appearance of Parvalbumin-positive interneurons in the early postnatal somatosensory cortex while cell numbers remained permanently reduced in Mct8/Oatp1c1 dko mice. Using fluorescence in situ hybridization on E12.5 embryonic brains, we detected reduced expression of sonic hedgehog signaling components in Mct8/Oatp1c1 dko embryos only. Moreover, we revealed spatially distinct expression patterns of both TH transporters at brain barriers at E12.5 by immunofluorescence. At later developmental stages, we uncovered a sequential expression of first Oatp1c1 in individual interneurons and then Mct8 in Parvalbumin-positive subtypes. Together, our results point to multiple cell-autonomous and noncell-autonomous mechanisms that depend on proper TH transport during cortical interneuron development.

Establishing an Adult Mouse Brain Hippocampal Organotypic Slice Culture System that Allows for Tracing and Pharmacological Manipulation of ex vivo Neurogenesis.

The function of the hippocampus depends on the process of adult hippocampal neurogenesis which underpins the exceptional neural plasticity of this structure, and is also frequently affected in CNS pathologies. Thus, manipulation of this process represents an important therapeutic goal. To identify potential strategies, organotypic adult brain slices are emerging as a valuable tool. Over the recent years, this methodology has been refined and here we present a combined protocol that brings together these refinements to enable long-term culture of adult hippocampal slices. We employ a sectioning technique that retains essential afferent inputs onto the hippocampus as well as serum-free culture conditions, so allowing an extended culture period. To sustain the neurogenic potential in the slices, we utilize the gliogenesis-inhibitor Indomethacin. Using EdU retention analysis enables us to assess the effects of pharmacological intervention on neurogenesis. With these improvements, we have established an easy and reliable method to study the effects of small molecules/drugs on proliferation and neuron formation ex vivo which will facilitate future discovery driven drug screenings.

Hippocampal Neurogenesis Requires Cell-Autonomous Thyroid Hormone Signaling.

Adult hippocampal neurogenesis is strongly dependent on thyroid hormone (TH). Whether TH signaling regulates this process in a cell-autonomous or non-autonomous manner remains unknown. To answer this question, we used global and conditional knockouts of the TH transporter monocarboxylate transporter 8 (MCT8), having first used FACS and immunohistochemistry to demonstrate that MCT8 is the only TH transporter expressed on neuroblasts and adult slice cultures to confirm a necessary role for MCT8 in neurogenesis. Both mice with a global deletion or an adult neural stem cell-specific deletion of MCT8 showed decreased expression of the cell-cycle inhibitor P27KIP1, reduced differentiation of neuroblasts, and impaired generation of new granule cell neurons, with global knockout mice also showing enhanced neuroblast proliferation. Together, our results reveal a cell-autonomous role for TH signaling in adult hippocampal neurogenesis alongside non-cell-autonomous effects on cell proliferation earlier in the lineage.

Tissue-Specific Function of Thyroid Hormone Transporters: New Insights from Mouse Models.

Thyroid hormone (TH) transporters are required for cellular transmembrane passage of TH and are thus mandatory for proper TH metabolism and action. Consequently, inactivating mutations in TH transporters such as MCT8 or OATP1C1 can cause tissue- specific changes in TH homeostasis. As the most prominent example, patients with MCT8 mutations exhibit elevated serum T3 levels, whereas their CNS appear to be in a TH deficient state. Here, we will briefly summarize recent studies of mice lacking Mct8 alone or in combination with the TH transporters Mct10 or Oatp1c1 that shed light on many aspects and pathogenic events underlying global MCT8 deficiency and also underscore the contribution of Mct10 and Oatp1c1 in tissue-specific TH transport processes. Moreover, development of conditional knock-out mice that allow a cell-specific inactivation of TH transporters in distinct tissues, disclosed cell-specific changes in TH signaling, thereby highlighting the pathophysiological significance of local control of TH action.

Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte-myelin dysfunction.

Although the underlying neurobiology of major mental illness (MMI) remains unknown, emerging evidence implicates a role for oligodendrocyte-myelin abnormalities. Here, we took advantage of a large family carrying a balanced t(1;11) translocation, which substantially increases risk of MMI, to undertake both diffusion tensor imaging and cellular studies to evaluate the consequences of the t(1;11) translocation on white matter structural integrity and oligodendrocyte-myelin biology. This translocation disrupts among others the DISC1 gene which plays a crucial role in brain development. We show that translocation-carrying patients display significant disruption of  white matter integrity compared with familial controls. At a cellular level, we observe dysregulation of key pathways controlling oligodendrocyte development and morphogenesis in induced pluripotent stem cell (iPSC) derived case oligodendrocytes. This is associated with reduced proliferation and a stunted morphology in vitro. Further, myelin internodes in a humanized mouse model that recapitulates the human translocation as well as after transplantation of t(1;11) oligodendrocyte progenitors were significantly reduced when  compared with controls. Thus we provide evidence that the t(1;11) translocation has biological effects at both the systems and cellular level that together suggest oligodendrocyte-myelin dysfunction.

Thyroid Hormone Transporters MCT8 and OATP1C1 Control Skeletal Muscle Regeneration.

Thyroid hormone (TH) transporters are required for the transmembrane passage of TH in target cells. In humans, inactivating mutations in the TH transporter MCT8 cause the Allan-Herndon-Dudley syndrome, characterized by severe neuromuscular symptoms and an abnormal TH serum profile, which is fully replicated in Mct8 knockout mice and Mct8/Oatp1c1 double-knockout (M/O DKO) mice. Analysis of tissue TH content and expression of TH-regulated genes indicate a thyrotoxic state in Mct8-deficient skeletal muscles. Both TH transporters are upregulated in activated satellite cells (SCs). In M/O DKO mice, we observed a strongly reduced number of differentiated SCs, suggesting an impaired stem cell function. Moreover, M/O DKO mice and mice lacking both transporters exclusively in SCs showed impaired skeletal muscle regeneration. Our data provide solid evidence for a unique gate-keeper function of MCT8 and OATP1C1 in SC activation, underscoring the importance of a finely tuned TH signaling during myogenesis.

Merlin Isoforms 1 and 2 Both Act as Tumour Suppressors and Are Required for Optimal Sperm Maturation.

The tumour suppressor Merlin, encoded by the gene NF2, is frequently mutated in the autosomal dominant disorder neurofibromatosis type II, characterised primarily by the development of schwannoma and other glial cell tumours. However, NF2 is expressed in virtually all analysed human and rodent organs, and its deletion in mice causes early embryonic lethality. Additionally, NF2 encodes for two major isoforms of Merlin of unknown functionality. Specifically, the tumour suppressor potential of isoform 2 remains controversial. In this study, we used Nf2 isoform-specific knockout mouse models to analyse the function of each isoform during development and organ homeostasis. We found that both isoforms carry full tumour suppressor functionality and can completely compensate the loss of the other isoform during development and in most adult organs. Surprisingly, we discovered that spermatogenesis is strictly dependent on the presence of both isoforms. While the testis primarily expresses isoform 1, we noticed an enrichment of isoform 2 in spermatogonial stem cells. Deletion of either isoform was found to cause decreased sperm quality as observed by maturation defects and head/midpiece abnormalities. These defects led to impaired sperm functionality as assessed by decreased sperm capacitation. Thus, we describe spermatogenesis as a new Nf2-dependent process. Additionally, we provide for the first time in vivo evidence for equal tumour suppressor potentials of Merlin isoform 1 and isoform 2.

The multispecific thyroid hormone transporter OATP1C1 mediates cell-specific sulforhodamine 101-labeling of hippocampal astrocytes.

Sulforhodamine 101 (SR101) is widely used for astrocyte identification, though the labeling mechanism remains unknown and the efficacy of labeling in different brain regions is heterogeneous. By combining region-specific isolation of astrocytes followed by transcriptome analysis, two-photon excitation microscopy, and mouse genetics, we identified the thyroid hormone transporter OATP1C1 as the SR101-uptake transporter in hippocampus and cortex.

Absence of TRH receptor 1 in male mice affects gastric ghrelin production.

TRH not only functions as a thyrotropin releasing hormone but also acts as a neuropeptide in central circuits regulating food intake and energy expenditure. As one suggested mode of action, TRH expressed in the caudal brainstem influences vagal activity by activating TRH receptor 1 (TRH-R1). In order to evaluate the impact of a diminished medullary TRH signaling on ghrelin metabolism, we analyzed metabolic changes of TRH-R1 knockout (R1ko) mice in response to 24 hours of food deprivation. Because R1ko mice are hypothyroid, we also studied eu- and hypothyroid wild-type (wt) animals and R1ko mice rendered euthyroid by thyroid hormone treatment. Independent of their thyroidal state, R1ko mice displayed a higher body weight loss than wt animals and a delayed reduction in locomotor activity upon fasting. Ghrelin transcript levels in the stomach as well as total ghrelin levels in the circulation were equally high in fasted wt and R1ko mice. In contrast, only wt mice responded to fasting with a rise in ghrelin-O-acyltransferase mRNA expression and consequently an increase in serum levels of acylated ghrelin. Together, our data suggest that an up-regulation of medullary TRH expression and subsequently enhanced activation of TRH-R1 in the vagal system represents a critical step in the stimulation of ghrelin-O-acyltransferase expression upon starvation that in turn is important for adjusting the circulating levels of acylated ghrelin to the fasting condition.

Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis.

Allan-Herndon-Dudley syndrome (AHDS), a severe form of psychomotor retardation with abnormal thyroid hormone (TH) parameters, is linked to mutations in the TH-specific monocarboxylate transporter MCT8. In mice, deletion of Mct8 (Mct8 KO) faithfully replicates AHDS-associated endocrine abnormalities; however, unlike patients, these animals do not exhibit neurological impairments. While transport of the active form of TH (T3) across the blood-brain barrier is strongly diminished in Mct8 KO animals, prohormone (T4) can still enter the brain, possibly due to the presence of T4-selective organic anion transporting polypeptide (OATP1C1). Here, we characterized mice deficient for both TH transporters, MCT8 and OATP1C1 (Mct8/Oatp1c1 DKO). Mct8/Oatp1c1 DKO mice exhibited alterations in peripheral TH homeostasis that were similar to those in Mct8 KO mice; however, uptake of both T3 and T4 into the brains of Mct8/Oatp1c1 DKO mice was strongly reduced. Evidence of TH deprivation in the CNS of Mct8/Oatp1c1 DKO mice included highly decreased brain TH content as well as altered deiodinase activities and TH target gene expression. Consistent with delayed cerebellar development and reduced myelination, Mct8/Oatp1c1 DKO mice displayed pronounced locomotor abnormalities. Intriguingly, differentiation of GABAergic interneurons in the cerebral cortex was highly compromised. Our findings underscore the importance of TH transporters for proper brain development and provide a basis to study the pathogenic mechanisms underlying AHDS.