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

• Published in: Molecular and cellular endocrinology 2018-12, Vol.478, p.62-76
• Main Authors: Domingues, Juliana Tonietto, Wajima, Carolinne Sayury, Cesconetto, Patricia Acordi, Parisotto, Eduardo Benedetti, Winkelmann-Duarte, Elisa, Santos, Karin dos, Saleh, Najla, Filippin-Monteiro, Fabíola Branco, Razzera, Guilherme, Mena Barreto Silva, Fátima Regina, Pessoa-Pureur, Regina, Zamoner, Ariane
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - metabolism; Animals; Animals, Newborn; Antigens, Nuclear - metabolism; Behavior, Animal; Biological Transport; Body Composition; Calcium; Cells, Cultured; Cerebral Cortex - enzymology; Cholinesterase; Cytoskeleton; Female; GFAP; Glial Fibrillary Acidic Protein - metabolism; Glucose - metabolism; Glutamate-Ammonia Ligase - metabolism; Glutamic Acid - metabolism; Hypothyroidism; Hypothyroidism - blood; Hypothyroidism - chemically induced; Hypothyroidism - physiopathology; L-Lactate Dehydrogenase - metabolism; Molecular Docking Simulation; Motor Activity; Nerve Tissue Proteins - metabolism; Oxidation-Reduction; Phosphorylation; Propylthiouracil; Rats, Wistar; Receptors, Cytoplasmic and Nuclear - metabolism; Redox imbalance; Sensorimotor Cortex - enzymology; Thyroid Gland - metabolism; Thyroid Hormones - blood
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2018.07.008

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. [Display omitted] •Congenital hypothyroidism disrupts glutamatergic and cholinergic neurotransmission.•Hypothyroidism affects the morphology and structure of sensorimotor cortex.•The mechanism of PTU action could involve the inactivation of TRβ.•Congenital hypothyroidism leads to redox imbalance.