Age-dependent evaluation of long-term depression responses in hyperthyroid rats: Possible roles of oxidative intracellular redox status.

Background: According to the free radical theory, a gradual accumulation of the free radicals normally produced in the body underlies the changes associated with aging. Thyroid hormones (THs) are related to oxidative stress not only due to their stimulation of metabolism but also due to their effects on antioxidant mechanisms. Thyroid dysfunction increases with age; thus, changes in TH levels in elderly individuals could be a factor affecting the development of neurodegenerative diseases. However, the relationship is not always clear, based on current evidence regarding synaptic plasticity.

Methods: Hippocampal long-term depression (LTD) and oxidative status in the hippocampus were evaluated at two different ages (2-3 and 12-14 months) in male rats. Rats were administered 0.2 mg/kg/day of l-thyroxine for 21 days starting at postnatal day 40 to induce hyperthyroidism. LTD was induced in the dentate gyrus using low frequency stimulation of the perforant pathway. Spectrophotometry was performed to measure catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA) levels, glutathione peroxidase (GPx) activity, and total nitrite/nitrate (tNOx) and nitric oxide synthase (NOS) levels.

Results: A reliable LTD was elicited in young rats with hyperthyroidism, while the same protocol could induce a small magnitude of synaptic LTD in the absence of spike-LTD in control rats. In aged rats, controls did not express LTD, but a significant LTP of spike was induced in the absence of synaptic LTD in hyperthyroid rats. While CAT levels were significantly decreased, MDA levels were increased in the aged groups compared to the corresponding young groups. Young rats with euthyroidism had significantly lower GPx activity than each of the hyperthyroid groups. There was no significant difference in SOD levels among the groups. Compared with aged rats, young rats exhibited a hyperthyroidism-induced decrease in NOS levels. Nevertheless, neither the main effects of age and thyroxine administration nor the interaction between these factors reached significance for tNOx.

Conclusion: These results indicate that hyperthyroidism-related changes in synaptic plasticity are modulated by aging. This modulation may explain the increased cognitive impairment in this disease at older ages, which probably depends on alterations in NOS levels.