Alterations in local thyroid hormone signaling in the hippocampus of the SAMP8 mouse at younger ages: association with delayed myelination and behavioral abnormalities.

The senescence-accelerated mouse (SAM) strains were established through selective inbreeding of the AKR/J strain based on phenotypic variations of aging and consist of senescence-prone (SAMP) and senescence-resistant (SAMR) strains. Among them, SAMP8 is considered as a model of neurodegeneration displaying age-associated learning and memory impairment and altered emotional status. Because adult hypothyroidism is one of the common causes of cognitive impairment and various psychiatric disorders, we examined the possible involvement of thyroid hormone (TH) signaling in the pathological aging of SAMP8 using the senescence-resistant SAMR1 as control. Although plasma TH levels were similar in both strains, a significant decrease in type 2 deiodinase (D2) gene expression was observed in the SAMP8 hippocampus from 1 to 8 months of age, which led to a 35-50% reductions at the protein level and 20% reduction of its enzyme activity at 1, 3, and 5 months. D2 is responsible for local conversion of thyroxine into transcriptionally active 3,5,3'-triiodothyronine (T3), so the results suggest a reduction in T3 level in the SAMP8 hippocampus. Attenuation of local TH signaling was confirmed by downregulation of TH-dependent genes and by immunohistochemical demonstration of delayed and reduced accumulation of myelin basic protein, the expression of which is highly dependent on TH. Furthermore, we found that hyperactivity and reduced anxiety were not age-associated but were characteristic of young SAMP8 before they start showing impairments in learning and memory. Early alterations in local TH signaling may thus underlie behavioral abnormalities as well as the pathological aging of SAMP8.