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Experimentally-induced maternal hypothyroidism alters enzyme activities and the sensorimotor cortex of the offspring rats

Authors:
Juliana Tonietto Domingues at Yale University
Juliana Tonietto Domingues
Patrícia Acordi Cesconetto at Universidade Federal de Santa Catarina
Patrícia Acordi Cesconetto
Ariane Zamoner at Universidade Federal de Santa Catarina
Ariane Zamoner
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Abstract

In this study, we used an experimental model of congenital hypothyroidism to show that deficient thyroid hormones (TH) disrupt different neurochemical, morphological and functional aspects in the cerebral cortex of 15-day-old offspring. Our results showing decreased glutamine synthetase (GS) activity and Ca2+ overload in the cerebral cortex of hypothyroid pups suggest misregulated glutamate metabolism associated with developmentally induced TH deficiency. The 14C-MeAIB accumulation indicates upregulated System A activity and glutamine uptake by neurons. Energy metabolism in hypothyroid cortical slices was preserved, as demonstrated by unaltered glucose metabolism. We also found upregulated acetylcholinesterase activity, depleting acetylcholine from the synaptic cleft, pointing to disrupted cholinergic system. Increased reactive oxygen species (ROS) generation, lipid peroxidation, glutathione (GSH) depletion, which were associated with glutathione peroxidase, superoxide dismutase and gamma-glutamyltransferase downregulation suggest redox imbalance. Disrupted astrocyte cytoskeleton was evidenced by downregulated and hyperphosphorylated glial fibrillary acidic protein (GFAP). Morphological and structural characterization of the sensorimotor cerebral cortex (SCC) showed unaltered thickness of the SCC. However, decreased size of neurons on the layers II & III and IV in the right SCC and increased NeuN positive neurons in specific SCC layers, suggest that they are differently affected by the low TH levels during neurodevelopment. Hypothyroid pups presented increased number of foot-faults in the gridwalk test indicating affected motor functions. Taken together, our results show that congenital hypothyroidism disrupts glutamatergic and cholinergic neurotransmission, Ca2+ equilibrium, redox balance, cytoskeleton integrity, morphological and functional aspects in the cerebral cortex of young rats.
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13/03/2019
Experimentally-induced maternal hypothyroidism alters enzyme activities and the sensorimotor cortex of the offspring rats | Elsevie…
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Experimentally-induced maternal hypothyroidism alters enzyme activities and the sensorimotor cortex of the offspring rats | Elsevie…
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Experimentally-induced maternal hypothyroidism alters enzyme activities and the sensorimotor cortex of the offspring rats | Elsevie…
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Experimentally-induced maternal hypothyroidism alters enzyme activities and the sensorimotor cortex of the offspring rats | Elsevie…
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Experimentally-induced maternal hypothyroidism alters enzyme activities and the sensorimotor cortex of the offspring rats | Elsevie…
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Experimentally-induced maternal hypothyroidism alters enzyme activities and the sensorimotor cortex of the offspring rats | Elsevie…
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Experimentally-induced maternal hypothyroidism alters enzyme activities and the sensorimotor cortex of the offspring rats | Elsevie…
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Experimentally-induced maternal hypothyroidism alters enzyme activities and the sensorimotor cortex of the offspring rats | Elsevie…
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Experimentally-induced maternal hypothyroidism alters enzyme activities and the sensorimotor cortex of the offspring rats | Elsevie…
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Experimentally-induced maternal hypothyroidism alters enzyme activities and the sensorimotor cortex of the offspring rats | Elsevie…
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Experimentally-induced maternal hypothyroidism alters enzyme activities and the sensorimotor cortex of the offspring rats | Elsevie…
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Experimentally-induced maternal hypothyroidism alters enzyme activities and the sensorimotor cortex of the offspring rats | Elsevie…
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Experimentally-induced maternal hypothyroidism alters enzyme activities and the sensorimotor cortex of the offspring rats | Elsevie…
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Experimentally-induced maternal hypothyroidism alters enzyme activities and the sensorimotor cortex of the offspring rats | Elsevie…
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Experimentally-induced maternal hypothyroidism alters enzyme activities and the sensorimotor cortex of the offspring rats | Elsevie…
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... Developmental TH deficiency induces an important delay in the maturation of the cholinergic system in several brain regions. It induces a reduction in the expression of the muscarinic receptor 1, as well as a reduced activity of choline acetyltransferase and an increased activity of acetylcholinesterase (Domingues et al., 2018;Koromilas et al., 2010). These alterations decrease acetylcholine and increase choline levels, modifying the homeostasis of the cholinergic system during neurodevelopment. ...
... TH also affect other neurotransmitter systems. Hypothyroid condition during brain development delays the maturation of the dopaminergic system (Vaccari et al., 1990), particularly related to a reduction in striatal D1 receptors and altered dopamine metabolism, and affects glutamatergic neurotransmission (Domingues et al., 2018), mainly by alterations in glutamineeglutamate metabolism in astroglial cells. ...
Endocrine aspects of development. Thyroid hormone actions in neurological processes during brain development
Chapter
  • Jan 2021
Hormones are key factors throughout neurodevelopment, and thyroid hormones are essential for a correct maturation of the nervous system. Thyroid hormones’ pleiotropic actions during brain development include the regulation of cell generation and survival, differentiation, migration, growth, and retraction of cellular processes, synaptogenesis, myelination, and establishment of neuronal circuits. Indeed, thyroid hormones act on different progenitor cells, glial cells, and neurons subtypes, at specific regional and temporal patterns. They are key factors involved in the regulation of the expression of target genes, including cell cycle proteins, growth factors, and neurotrophins, cytoskeleton proteins, axon guidance and synaptogenesis-related proteins, myelin proteins, and enzymes related to neurotransmitter metabolism. In the fetus, the maternal thyroid hormone supply is essential for a correct neurodevelopment, until the fetal thyroid gland is functional. Thyroid hormones deficiency during brain development induces mild to devastating impairments on the neurological outcome of the offspring depending on the severity of the deficiency, its duration, and the time window affected.
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... TH deficiency causes wide range abnormalities in the offspring including defective in the neuronal migration, reduced myelination, growth of axons, and dendrites which are associated with motor, visual, and auditory functions [20]. Hypothyroidism also associated with other histomorphological changes within the cerebellum, involving fostered neuronal death with the internal granular layer, fostered perdurance of the external granular layer, defects within granular cell migration, impaired Purkinje cell dendritogenesis, delayed myelination, and increased cell apoptosis [21]. ...
... Recent results demonstrated that CH induces reactive oxygen species production, which is affiliated with LPO and GSH depletion, these results suggest that hypothyroidism causes redox imbalance and oxidative stress in the cerebral cortex of immature rats. It has been reported that increased oxidative stress in granulosa cell and oocyte necroptosis due to RIPK signaling pathways [20]. In a study RIPK3 has been associated with microvascular ischemia-reperfusion injury through increased xanthine oxidase-dependent oxidative damage. ...
Necroptosis mediated by receptor interacting protein kinase 3 as critical player in experimental congenital hypothyroidism related neuronal damage
Article
Full-text available
  • Oct 2021
Objective: Congenital hypothyroidism (CH) is literally described as congenital thyroid hormone imperfection. The primary objective of this research was to reveal the possible relation between receptor-acting protein kinase 3 (RIPK3) activity and neuronal damages in rat pups with CH. In addition, we evaluated the favorable impacts of 3.6-dibromo-α-([phenylamino] methyl)-9H-carbazole-9-ethanol (P7C3) reducing RIPK3 activity. Methods: Adult rats were accordingly assigned into four groups: Group 1, which is called congenital hypothyroid; Group 2, which is called congenital hypothyroid administered P7C3; Group 3, called CH administered P7C3 and L-thyroxine; and Group 4, control group. RIPK3 level in plasma concentration and its expression in tissue was determined in all groups. Results: Increased RIPK3 expressions were detected as high in the CH group when it is compared to the control group. Furthermore; the expressions in neuronal cytoplasm were found similar among Groups II and III. RIPK3 expressions in those two groups were relatively higher than in the control group. Most reacted parts of the brain were especially Purkinje cells in the cerebellum. Conclusion: It is concluded that there is excellent parallelism among damaged neurons and high RIPK3 activity in CH pathogenesis. P7C3 compounds may have a safeguarding impact on CH due to decreasing RIPK3 activity.
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... an animal model of congenital hypothyroidism (Domingues et al., 2018;Kumar et al., 2018). It is worth noting that the decrease in GFAP density associated with increased AChE activity and oxidative stress demonstrated disrupts of cholinergic transmission (Domingues et al., 2018). ...
... an animal model of congenital hypothyroidism (Domingues et al., 2018;Kumar et al., 2018). It is worth noting that the decrease in GFAP density associated with increased AChE activity and oxidative stress demonstrated disrupts of cholinergic transmission (Domingues et al., 2018). ...
Neuroprotection elicited by resveratrol in a rat model of hypothyroidism: Possible involvement of cholinergic signaling and redox status
Article
  • Jan 2021
  • MOL CELL ENDOCRINOL
Both the cholinergic pathway and oxidative stress are important mechanisms involved in the pathogenesis of hypothyroidism, a condition characterized by low levels of thyroid hormone that predispose the patient to brains dysfunction. Phenolic compounds have numerous health benefits, including antioxidant activity. This study evaluates the preventive effects of resveratrol in the cholinergic system and redox status in rats with methimazole-induced hypothyroidism. Hypothyroidism increases acetylcholinesterase (AChE) activity and density in the cerebral cortex and hippocampus and decreases the α7 and M1 receptor densities in the hippocampus. Hypothyroidism also increases cellular levels of reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS), but reduces total thiol content, and catalase and superoxide dismutase activities in the serum. In the cerebral cortex and hippocampus, hypothyroidism increases the levels of ROS and nitrites. In this study, resveratrol (50 mg/kg) treatment prevented the observed increase in AChE in the cerebral cortex, and increased the protein levels of NeuN, a marker of mature neurons. Resveratrol also prevented changes in serum ROS levels and brain structure, as well as the levels of TBARS, total thiol content, and serum catalase enzyme activity. These collective findings suggest that resveratrol has a high antioxidant capacity and can restore hypothyroidism-triggered alterations related to neurotransmission. Thus, it is a promising agent for the prevention of brain damage resulting from hypothyroidism.
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... Its reduction could induce the upregulation of the phosphatidylinositol 3-kinase/ protein kinase B (PI3K/AKT) pathway, affect the amount of the tight junction protein claudin-1, and promote intestinal permeability . Some studies have shown glutamate-glutamine cycle abnormalities in the hippocampus of hypothyroid rats, and glutamate accumulation excessively activates neuronal cells, leading to injury or even death (Cattani et al., 2013;Domingues et al., 2018). This could explain why the hypothyroid offspring of pregnant women have a greater risk of neurological disorders. ...
Gut microbiome characteristics of women with hypothyroidism during early pregnancy detected by 16S rRNA amplicon sequencing and shotgun metagenomic
Article
Full-text available
  • Aug 2024
Objective This study aimed to explore the correlation between microbiota dysbiosis and hypothyroidism in early pregnancy by 16S rRNA amplicon sequencing combined with metagenomic sequencing. Methods Sixty pregnant women (30 with hypothyroidism and 30 normal controls) were recruited for 16S rRNA amplicon sequencing, and 6 patients from each group were randomly selected for metagenomic sequencing to assess the gut microbiome profile. Results The 16S rRNA results showed that beta-diversity in the hypothyroidism group was decreased. The relative abundances of the Prevotella and Paraprevotella genera increased in the hypothyroidism group, and Blautia predominated in the controls. The metagenomics results revealed that Prevotella_stercorea_CAG_629, Prevotella_hominis, Prevotella_sp_AM34_19LB, etc. were enriched in the hypothyroidism group at the species level. Functional analysis revealed that the pyridoxal 5’-phosphate synthase pdxT subunit module was decreased, and the short-chain fatty acid (SCFA) transporter and phospholipase/carboxylesterase modules were strongly enriched in the hypothyroidism group. Hypothyroidism patients had increased C-reactive protein (CRP), interleukin-2 (IL-2), IL-4, IL-10, and tumor necrosis factor (TNF)-α levels. The pyridoxal 5’-phosphate synthase pdxT subunit, the SCFA transporter, and the phospholipase/carboxylesterase module were associated with different Prevotella species. Conclusion In early pregnancy, women with hypothyroidism exhibit microbiota dysbiosis, and Prevotella may affect the metabolism of glutamate, SCFA, and phospholipases, which could be involved in the development of hypothyroidism during pregnancy.
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... The impact of hypothyroidism in utero has been extensively studied in rodents using antithyroid medications such as methimazole (MMI) and propylthiouracil, which are drugs that inhibit thyroid hormone production by interfering with the activity of thyroid peroxidase [4]. Such studies have clearly demonstrated deleterious effects of hypothyroidism including altered neural development [5] and modulations in other fetal endocrine systems [6,7]. Studies in thyroidectomized fetal sheep have additionally shown that hypothyroidism alters muscle composition and functionality [8], as well as bone development and ossification [9]. ...
Late gestation fetal hypothyroidism alters cell cycle regulation across multiple organ systems
Article
Full-text available
  • Jun 2024
  • BMC Vet Res
Background Hypothyroidism is a common endocrine disruption observed in utero that adversely affects fetal growth and maturation leading to long-term impacts on health; however, the exact molecular mechanisms by which these deleterious effects occur are unknown. We hypothesize that fetal hypothyroidism during late gestation will disrupt cell cycle regulation in a tissue-specific manner. To evaluate this, eight pregnant gilts were dosed with either methimazole or an equivalent negative control during days 85–106 out of 114 days of gestation (n = 4/group). Following treatment, the gilts were humanely euthanized, and tissue samples of fetal heart, ileum, kidney, lung, liver, muscle, spleen, and thymus taken from two male and two female fetuses (n = 32) from each gilt. Results The relative expression of three cell cycle promoters (CDK1, CDK2, and CDK4), and one cell cycle inhibitor (CDKN1A) was compared in each tissue to determine the effect of hypothyroidism on the developing fetus. All of the eight tissues examined experienced at least one significant up- or downregulation in the expression of the aforementioned genes as a result of treatment with methimazole. Substantial changes were observed in the liver and muscle, with the latter experiencing significant downregulations of CDK1, CDK2, and CDK4 as a result of treatment. In addition, all tissues were examined for changes in protein content, which further elucidated the impact of hypothyroidism on the fetal liver by the observation of a marked increase in protein content in the methimazole-treated group. Finally, the heart and liver were histologically examined for evidence of cellular hyperplasia and hypertrophy by measuring average nuclei density and size in each tissue, with the results showing a significant decrease in average nuclei size in the liver of hypothyroid fetuses. Conclusions Collectively, these findings indicate the occurrence of organ-specific disruptions in cell cycle progression as a result of in utero hypothyroidism, which may explain the long term and widespread effects of hypothyroidism on fetal development.
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... However, the offspring exposed to thyroid hormone deficiency in utero has been reported lower weight gain or no significant changes in weight gain. [83][84][85] While this may reflect the model we used, we note that the rodent type, the dose and type of antithyroid drugs, the administrated period, and the degree of thyroid hormone deficiency may be reasons for this different finding. Indeed, gestational hypothyroidism affects glucose metabolism and increases susceptibility to diabetes in the offspring. ...
HDAC1/2/3‐mediated downregulation of neurogranin is involved in cognitive impairment in offspring exposed to maternal subclinical hypothyroidism
Article
Full-text available
Subclinical hypothyroidism (SCH) in pregnancy is the most common form of thyroid dysfunction in pregnancy, which can affect fetal nervous system development and increase the risk of neurodevelopmental disorders after birth. However, the mechanism of the effect of maternal subclinical hypothyroidism on fetal brain development and behavioral phenotypes is still unclear and requires further study. In this study, we constructed a mouse model of maternal subclinical hypothyroidism by exposing dams to drinking water containing 50 ppm propylthiouracil (PTU) during pregnancy and found that its offspring were accompanied by severe cognitive deficits by behavioral testing. Mechanistically, gestational SCH resulted in the upregulation of protein expression and activity of HDAC1/2/3 in the hippocampus of the offspring. ChIP analysis revealed that H3K9ac on the neurogranin (Ng) promoter was reduced in the hippocampus of the offspring of SCH, with a significant reduction in Ng protein, leading to reduced expression levels of synaptic plasticity markers PSD95 (a membrane‐associated protein in the postsynaptic density) and SYN (synaptophysin, a specific marker for presynaptic terminals), and impaired synaptic plasticity. In addition, administration of MS‐275 (an HDAC1/2/3‐specific inhibitor) to SCH offspring alleviated impaired synaptic plasticity and cognitive dysfunction in offspring. Thus, our study suggests that maternal subclinical hypothyroidism may mediate offspring cognitive dysfunction through the HDAC1/2/3‐H3K9ac‐Ng pathway. Our study contributes to the understanding of the signaling mechanisms underlying maternal subclinical hypothyroidism‐mediated cognitive impairment in the offspring.
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... Given that CH alters Ca 2+ influx into neurons of the cortex and hippocampus of developing rats [26,27], which is involved in the inactivation of CaMKIV [28,29], it is assumed that the EGR3/BDNF axis may be affected by the dysregulation of CaMKIV, as the calmodulin-dependent protein kinase is proved to be active in the regulation of EGRs [30]. Therefore, the CaMKIV/EGR3 signal axis is possibly associated with CH-mediated deficient hippocampus development. ...
CaMKIV mediates spine growth deficiency of hippocampal neurons by regulation of EGR3/BDNF signal axis in congenital hypothyroidism
Article
Full-text available
  • Dec 2022
Congenital hypothyroidism (CH) will cause cognitive impairment in the condition of delayed treatment. The hippocampus is one of the most affected tissues by CH, in which the functional structures of hippocampal neurons manifest deficiency due to aberrant expression of effector molecules. The Ca ²⁺ /Calmodulin-dependent protein kinase, CaMKIV, is downregulated in the hippocampal neurons, influencing the growth of dendritic spines in response to CH. However, the underlying mechanism is not fully elucidated. In the present study, the early growth response factor 3 (EGR3) was regulated by CaMKIV in the hippocampal neurons of CH rat pups, as was analyzed by transcriptome sequencing and in vitro cell experiments. EGR3 localized within hippocampal neurons in CA1, CA3, and dentate gyrus regions. Deficient EGR3 in the primary hippocampal neurons significantly reduced the density of dendritic spines by downregulating the expression of BDNF, and such effects could be rescued by supplementing recombinant BDNF protein. Taken together, CH mediates cognitive impairment of pups through the inactivation of CaMKIV in the hippocampal neurons, which decreases the expression of EGR3 and further reduces the production of BDNF, thereby impairing the growth of dendritic spines. Identifying CaMKIV/EGR3/BDNF pathway in the hippocampal neurons in the context of CH will benefit the drug development of intellectual disability caused by CH.
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... Analogically to insulin resistance, despite elevated blood leptin, it does not mediate its effects, in general due to the impairment either of leptin transport into the brain, or the central response [28] . The obesity-associated hyperleptinemia was shown to promote hypertension in rats through the mechanism depending on hypothalamic astroglial hypoxia-inducible factor 1αvascular endothelial growth factor (HIF1α-VEGF) [65] , and not via the neuronal (pro)renin receptor, a component of the brain renin-angiotensin system [66] . ...
The contribution of astrocytes to obesity-associated metabolic disturbances
Article
Full-text available
  • Aug 2022
Obesity is a worldwide health, economic and social concern, despite efforts made to counteract the spreading wave of eating and nourishment-associated disorders. The review aims to show how the glial cells, astrocytes, contribute to the central regulation of appetite and energy metabolism. The hypothalamus is the brain center responsible for nutrients and nutritional hormone sensing, signal processing, and execution of metabolic and behavioral responses, directed at sustaining energy homeostasis. The astrocytes are endowed with receptors, transporters and enzymatic machinery responsible for glucose, lactate, fatty acids, ketone bodies, as well as leptin or ghrelin transport and metabolism, and that render them supporters and partners for neurons in governing the brain and body energy intake and expenditure. However, the role of astrocytes associated with brain energy metabolism reaches far beyond simple fuel contingent-they contribute to cognitive performance. The cognitive decline which often accompanies high fat- and/or high-calorie diets and correlates with neuroinflammation and astrogliosis, is a major concern. The last two decades of research enabled us to acknowledge the astroglia in obesity-associated dysfunctions and to investigate astrocytes as contributors to the pathology, as well as targets for therapy.
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... This suggests that even normal level of T3 in the CSF, astrocyte-TH dysregulation in the brain due to genetic modifi cation contributes to dementia in the elderly. Energy metabolism in hypothyroid brain leads to disruption in astrocyte cytoskeleton as well as glutamatergic and cholinergic neurotransmission, Ca 2+ equilibrium, redox balance, morphological and functional aspects in the cerebral cortex even in young rats from maternal hypothyroidism [79]. ...
Glioendocrine System: Effects of Thyroid Hormones in Glia and their Functions in the Central Nervous System
Article
Full-text available
  • Jun 2020
Glial cells play a significant role in the link between the endocrine and nervous systems. Among hormones, thyroid hormones (THs) are critical for the regulation of development and differentiation of neurons and glial cells, and hence for development and function of the central nervous system (CNS). THs are transported into the CNS, metabolized in astrocytes and affect various cell types in the CNS including astrocyte itself. Since 3,3’,5-triiodo-L-thyronine (T3) is apparently released from astrocytes in the CNS, it is a typical example of glia-endocrine system. The prevalence of thyroid disorders increases with age. Both hypothyroidism and hyperthyroidism are reported to increase the risk of cognitive impairment or Alzheimer’s disease (AD). Therefore, understanding the neuroglial effects of THs may help to solve the problem why hypothyroidism or hyperthyroidism may cause mental disorders or become a risk factor for cognitive impairment. In this review, THs are focused among wide variety of hormones related to brain function, and recent advancement in glioendocrine system is described.
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... This suggests that even normal levels of T3 in the CSF, astrocyte-TH dysregulation in the brain due to genetic modification contribute to dementia in the elderly. Energy metabolism in hypothyroid brain leads to disruption in astrocyte cytoskeleton as well as glutamatergic and cholinergic neurotransmission, Ca 2+ equilibrium, redox balance, morphological and functional aspects in the cerebral cortex even in young rats from maternal hypothyroidism [147]. ...
Metabolic Plasticity of Astrocytes and Aging of the Brain
Article
Full-text available
  • Feb 2019
  • INT J MOL SCI
As part of the blood-brain-barrier, astrocytes are ideally positioned between cerebral vasculature and neuronal synapses to mediate nutrient uptake from the systemic circulation. In addition, astrocytes have a robust enzymatic capacity of glycolysis, glycogenesis and lipid metabolism, managing nutrient support in the brain parenchyma for neuronal consumption. Here, we review the plasticity of astrocyte energy metabolism under physiologic and pathologic conditions, highlighting age-dependent brain dysfunctions. In astrocytes, glycolysis and glycogenesis are regulated by noradrenaline and insulin, respectively, while mitochondrial ATP production and fatty acid oxidation are influenced by the thyroid hormone. These regulations are essential for maintaining normal brain activities, and impairments of these processes may lead to neurodegeneration and cognitive decline. Metabolic plasticity is also associated with (re)activation of astrocytes, a process associated with pathologic events. It is likely that the recently described neurodegenerative and neuroprotective subpopulations of reactive astrocytes metabolize distinct energy substrates, and that this preference is supposed to explain some of their impacts on pathologic processes. Importantly, physiologic and pathologic properties of astrocytic metabolic plasticity bear translational potential in defining new potential diagnostic biomarkers and novel therapeutic targets to mitigate neurodegeneration and age-related brain dysfunctions.
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Effects of thyroid hormones on thermogenesis and energy partitioning
Article
Full-text available
  • Feb 2018
Thyroid hormones (TH) are of central importance for thermogenesis, energy homeostasis, and metabolism. Here we will discuss these aspects by focussing on the physiological aspects of TH-dependent regulation in response to cold exposure and fasting which will be compared to alterations in primary hyper- and hypothyroidism. In particular, we will summarise current knowledge on regional thyroid hormone status in the central nervous system (CNS) and in peripheral cells. In contrast to hyper- and hypothyroidism, where parallel changes are observed, local alterations in the CNS differ to peripheral compartments when induced by cold exposure or fasting. Cold exposure is associated with low hypothalamic TH concentrations but increased TH levels in the periphery. Fasting results in a reversed TH pattern. Primary hypothyroidism and hyperthyroidism disrupt these fine-tuned adaptive mechanisms and both, the hypothalamus and the periphery, will have the same TH status. These important mechanisms need to be considered when discussing thyroid hormone replacement and other therapeutical interventions to modulate TH status.
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A NMDA-receptor calcium influx assay sensitive to stimulation by glutamate and glycine/D-serine
Article
Full-text available
  • Dec 2017
N-methyl-D-aspartate-receptors (NMDARs) are ionotropic glutamate receptors that function in synaptic transmission, plasticity and cognition. Malfunction of NMDARs has been implicated in a variety of nervous system disorders, making them attractive therapeutic targets. Overexpression of functional NMDAR in non-neuronal cells results in cell death by excitotoxicity, hindering the development of cell-based assays for NMDAR drug discovery. Here we report a plate-based, high-throughput approach to study NMDAR function. Our assay enables the functional study of NMDARs with different subunit composition after activation by glycine/D-serine or glutamate and hence presents the first plate-based, high throughput assay that allows for the measurement of NMDAR function in glycine/D-serine and/or glutamate sensitive modes. This allows to investigate the effect of small molecule modulators on the activation of NMDARs at different concentrations or combinations of the co-ligands. The reported assay system faithfully replicates the pharmacology of the receptor in response to known agonists, antagonists, positive and negative allosteric modulators, as well as the receptor’s sensitivity to magnesium and zinc. We believe that the ability to study the biology of NMDARs rapidly and in large scale screens will enable the identification of novel therapeutics whose discovery has otherwise been hindered by the limitations of existing cell based approaches.
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Functional Identification of Activity‐Regulated, High‐Affinity Glutamine Transport in Hippocampal Neurons Inhibited by Riluzole
Article
Full-text available
Glutamine (Gln) is considered the preferred precursor for the neurotransmitter pool of glutamate (Glu), the major excitatory transmitter in the mammalian CNS . Here, an activity‐regulated, high‐affinity Gln transport system is described in developing and mature neuron‐enriched hippocampal cultures that is potently inhibited by riluzole ( IC 50 1.3 ± 0.5 μM), an anti‐glutamatergic drug, and is blocked by low concentrations of 2‐(methylamino)isobutyrate (Me AIB ), a system A transport inhibitor. K ⁺ ‐stimulated Me AIB transport displays an affinity ( K m ) for Me AIB of 37 ± 1.2 μM, saturates at ~ 200 μM, is dependent on extracellular Ca ²⁺ , and is blocked by inhibition of voltage‐gated Ca ²⁺ channels. Spontaneous Me AIB transport is also dependent on extracellullar Ca ²⁺ and voltage‐gated calcium channels, but is also blocked by the Na ⁺ channel blocker tetrodotoxin, by Glu receptor antagonists, and by GABA indicating its dependence on intact neural circuits driven by endogenous glutamatergic activity. The transport of Me AIB itself does not rely on Ca ²⁺ , but on Na ⁺ ions, and is pH sensitive. Activity‐regulated, riluzole‐sensitive spontaneous and K ⁺ ‐stimulated transport is minimal at 7–8 days in vitro , coordinately induced during the next 2 weeks and is maximally expressed by days in vitro > 20; the known period for maturation of the Glu/Gln cycle and regulated pre‐synaptic Glu release. Competition analyses with various amino acids indicate that Gln is the most likely physiological substrate. Activity‐regulated Gln/Me AIB transport is not observed in astrocytes. The functional identification of activity‐regulated, high‐affinity, riluzole‐sensitive Gln/Me AIB transport in hippocampal neurons may have important ramifications in the neurobiology of activity‐stimulated pre‐synaptic Glu release, the Glu/Gln cycle between astrocytes and neurons, and neuronal Glu‐induced excitotoxicity. image Cover Image for this issue: doi: 10.1111/jnc.13805 .
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Contributions of system A subtypes to α-methylaminoisobutyric acid uptake by placental microvillous membranes of human and rat
Article
Full-text available
  • Apr 2017
  • AMINO ACIDS
System A consists of three subtypes, sodium-coupled neutral amino acid transporter 1 (SNAT1), SNAT2, and SNAT4, which are all expressed in the placenta. The aim of this study was to evaluate the contributions of each of the three subtypes to total system A-mediated uptake in placental MVM of human and rat, using betaine and l-arginine as subtype-selective inhibitors of SNAT2 and SNAT4, respectively. Appropriate concentrations of betaine and l-arginine for subtype-selective inhibition in SNAT-overexpressing cells were identified. It was found that 10 mM betaine specifically and almost completely inhibited human and rat SNAT2-mediated [¹⁴C]α-methylaminoisobutyric acid ([¹⁴C]MeAIB) uptake, while 5 mM l-arginine specifically and completely inhibited [³H]glycine uptake via human SNAT4, as well as [¹⁴C]MeAIB uptake via rat SNAT4. In both human and rat placental MVM vesicles, sodium-dependent uptake of [¹⁴C]MeAIB was almost completely inhibited by 20 mM unlabeled MeAIB. l-Arginine (5 mM) partly inhibited the uptake in humans, but hardly affected that in rats. Betaine (10 mM) partly inhibited the uptake in rats, but hardly affected it in humans. These results suggest that SNAT1 is most likely the major contributor to system A-mediated MeAIB uptake by human and rat MVM vesicles and that the remaining uptake is mainly mediated by SNAT4 in humans and SNAT2 in rats. Thus, inhibition studies using betaine and l-arginine are useful to characterize the molecular mechanisms of system A-mediated transport.
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A temporary compendium of thyroid hormone target genes in brain
Article
Full-text available
  • Jan 2014
  • Biochim Biophys Acta
Background: Thyroid hormone controls a number of developmental and physiological processes in the brain by directly acting on gene expression. Transcriptome analyses in rodent identified a number of thyroid hormone regulated genes in several brain areas at different stages. Genome wide analysis of chromatin occupancy in a neural cell line also identified a subset of genes which transcription is likely to be directly regulated by thyroid hormone receptors in neurons. However, the abundance of these data and apparent discrepancies between studies brought some confusion. Results: We present here a meta-analysis of available data to identify recurrent themes in thyroid hormone action in brain cells. This provides a curated list of 734 regulated genes in rodent brain, and highlights a small number of likely direct target genes. Some of these genes are also regulated in amphibians during metamorphosis.
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Effects of Zinc Supplementation in Neonatal Hypothyroidism and Cerebellar Distortion Induced by Maternal Carbimazole
Article
Full-text available
  • Aug 2016
The aim of this study is to investigate the protective role of Zn on thyroid function and cerebellum impairments induced by carbimazole (CMI) in neonats at PND 28. Animals were divided into four groups: group I acts as control; group II received carbimazole(1.35mg/kg.b.wCMI) only; group III received Zn as zinc sulphate (3mg/kg.b.w) and group IV received Zn and CMI. The administration of maternal CMI caused significant decrease in serum T4, T3 and growth hormone (GH) levels and significant increase in serum TSH levels in both dams and their newborns relative to control group. While in Zinc-hypothyroid group, a reverse pattern was noticed for all previous parameters comparing with hypothyroid group. Maternal CMI administration caused significant decrease in GSH, SOD, GPX, CAT and t-SH of cerebellum and increased prooxidant levels including MDA, H 2 O 2 and NO while Zn administration to hypothyroid dams reversed this effect. CMI administration caused some degeneration and deformation innewborns cerebellum while zinc supplementation to CMI group enhanced structure, length, number and size of purkinje cells, also increase size of the granular layer.Our results indicated thatzinc has an improvement role on THs levels and histoarchiture of cerebellumdue to its antioxidant role.
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Reverse T 3 interacts with αvβ3 integrin receptor and restores enzyme activities in the hippocampus of hypothyroid developing rats: Insight on signaling mechanisms
Article
  • Jul 2018
  • MOL CELL ENDOCRINOL
In the present study we provide evidence that 3,3',5'-triiodothyronine (reverse T3, rT3) restores neurochemical parameters induced by congenital hypothyroidism in rat hippocampus. Congenital hypothyroidism was induced by adding 0.05% propylthiouracil in the drinking water from gestation day 8 and continually up to lactation day 15. In the in vivo rT3 exposure, hypothyroid 12-day old pups were daily injected with rT3 (50 ng/kg body weight) or saline until day 14. In the ex vivo rT3 treatment, hippocampal slices from 15-day-old hypothyroid pups were incubated for 30 min with or without rT3 (1 nM). We found that ex vivo and/or in vivo exposure to rT3 failed in restoring the decreased (14)C-glutamate uptake; however, restored the phosphorylation of glial fibrillary acidic protein (GFAP), (45)Ca(2+) influx, aspartate transaminase (AST), glutamine synthetase (GS) and gamma-glutamate transferase (GGT) activities, as well as glutathione (GSH) levels in hypothyroid hippocampus. In addition, rT3 improved (14)C-2-deoxy-D-glucose uptake and lactate dehydrogenase (LDH) activity. Receptor agonists/antagonists (RGD peptide and AP-5), kinase inhibitors of p38MAPK, ERK1/2, CaMKII, PKA (SB239063, PD98059, KN-93 and H89, respectively), L-type voltage-dependent calcium channel blocker (nifedipine) and intracellular calcium chelator (BAPTA-AM) were used to determine the mechanisms of the nongenomic rT3 action on GGT activity. Using molecular docking analysis, we found rT3 interaction with αvβ3 integrin receptors, nongenomically activating signaling pathways (PKA, CaMKII, p38MAPK) that restored GGT activity. We provide evidence that rT3 is an active TH metabolite and our results represent an important contribution to elucidate the nonclassical mechanism of action of this metabolite in hypothyroidism.
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Hypothyroidism in utero stimulates pancreatic beta cell proliferation and hyperinsulinaemia in the ovine fetus during late gestation
Article
Key points Thyroid hormones are important regulators of growth and maturation before birth, although the extent to which their actions are mediated by insulin and the development of pancreatic beta cell mass is unknown. Hypothyroidism in fetal sheep induced by removal of the thyroid gland caused asymmetric organ growth, increased pancreatic beta cell mass and proliferation, and was associated with increased circulating concentrations of insulin and leptin. In isolated fetal sheep islets studied in vitro, thyroid hormones inhibited beta cell proliferation in a dose‐dependent manner, while high concentrations of insulin and leptin stimulated proliferation. The developing pancreatic beta cell is therefore sensitive to thyroid hormone, insulin and leptin before birth, with possible consequences for pancreatic function in fetal and later life. The findings of this study highlight the importance of thyroid hormones during pregnancy for normal development of the fetal pancreas. Abstract Development of pancreatic beta cell mass before birth is essential for normal growth of the fetus and for long‐term control of carbohydrate metabolism in postnatal life. Thyroid hormones are also important regulators of fetal growth, and the present study tested the hypotheses that thyroid hormones promote beta cell proliferation in the fetal ovine pancreatic islets, and that growth retardation in hypothyroid fetal sheep is associated with reductions in pancreatic beta cell mass and circulating insulin concentration in utero. Organ growth and pancreatic islet cell proliferation and mass were examined in sheep fetuses following removal of the thyroid gland in utero. The effects of triiodothyronine (T3), insulin and leptin on beta cell proliferation rates were determined in isolated fetal ovine pancreatic islets in vitro. Hypothyroidism in the sheep fetus resulted in an asymmetric pattern of organ growth, pancreatic beta cell hyperplasia, and elevated plasma insulin and leptin concentrations. In pancreatic islets isolated from intact fetal sheep, beta cell proliferation in vitro was reduced by T3 in a dose‐dependent manner and increased by insulin at high concentrations only. Leptin induced a bimodal response whereby beta cell proliferation was suppressed at the lowest, and increased at the highest, concentrations. Therefore, proliferation of beta cells isolated from the ovine fetal pancreas is sensitive to physiological concentrations of T3, insulin and leptin. Alterations in these hormones may be responsible for the increased beta cell proliferation and mass observed in the hypothyroid sheep fetus and may have consequences for pancreatic function in later life.
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Structural aspects of thyroid hormone binding to proteins and competitive interactions with natural and synthetic compounds
Article
  • Jan 2017
Thyroid hormones and their metabolites constitute a vast class of related iodothyronine compounds that contribute to the regulation of metabolic activity and cell differentiation. They are in turn transported, transformed and recognized as signaling molecules through binding to a variety of proteins from a wide range of evolutionary unrelated protein families, which renders these proteins and their iodothyronine binding sites an example for extensive convergent evolution. In this review, we will briefly summarize what is known about iodothyronine binding sites in proteins, the modes of protein/iodothyronine interaction, and the ligand conformations. We will then discuss physiological and synthetic compounds, including popular drugs and food components, that can interfere with iodothyronine binding and recognition by these proteins. The discussion also includes compounds persisting in the environment and acting as endocrine disrupting chemicals.
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