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

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 Ca overload in the cerebral cortex of hypothyroid pups suggest misregulated glutamate metabolism associated with developmentally induced TH deficiency. The C-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, Ca equilibrium, redox balance, cytoskeleton integrity, morphological and functional aspects in the cerebral cortex of young rats.

Gestational hypothyroidism elicits more pronounced lipid dysregulation in mice than pre-pregnant hypothyroidism

“…Meanwhile, previous researches suggested that untreated pregnant women with hypothyroidism may develop hypothyroidism and diabetes in the years after pregnancy [24,25]. Considerable research efforts have been devoted to untreated experimentallyinduced maternal hypothyroidism that might have serious consequences for offspring development like behavior, skin, brain [26][27][28]. However, few systematic studies have concerned the interaction between hypothyroidism and gestation.…”

Necroptosis mediated by receptor interacting protein kinase 3 as critical player in experimental congenital hypothyroidism related neuronal damage

“…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.…”

Metabolic Plasticity of Astrocytes and Aging of the Brain

“…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].…”