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.