Age-related Learning And Memory Impairments In Adult-onset Hypothyroidism In Kunmimg Female Mice

Introduction Adult-onset hypothyroidism is relatively common in general population. Clinical observations have shown that hypothyroidism may associate with both neurological and behavioral abnormalities, such as impaired memory, depression and anxiety. The incidence of hypothyroidism increases with aging while the exactly onset time during adulthood that will influence on memory function is still an issue of debate. In the geriatric population, the link between dementia and hypothyroidism is controversial according to the published studies. Little is known about the effects of hypothyroidism on memory associated behaviors in nonhuman aged animal.It is well known that the requirement for Calcium/calmodulin-dependent protein kinase (CaMKll) activation in consolidation of memory. CaMKllαand CaMKllβare the two major isoforms of CaMKll expressed in the brain; The two isoforms have different sensitivities to Ca²⁺signals. CaMKllαis sensitive to higher levels of Ca²⁺ signals, while CaMKllβhas better sensitivity to lower levels of Ca²⁺ signals. Deleting of the CaMKllαgene in mice resulted in impairment in long-term potentiation (LTP) and also impairment in spatial memory.The actions of thyroid hormones are initiated by their interaction with thyroid hormone receptors (TR), which belong to a large superfamily of steroid hormone receptors other members of which include the sex steroid receptors, vitamin D receptors and retinoic acid receptors. There are many TR isoforms in brain. The change of the number, affinity constant, binding capacity or formation would affect the tissue responsiveness to thyroid hormones.Objietive The purpose of this study is to determine the onset effect of hypothyroidism on the memory during adulthood.Methods Three age groups of Kunming(KM) female mice were used, including 2, 8, and 15-month-old mice. Adult-onset hypothyroidism was made by adding propylthiouracil to drinking water and hypothyroid states were documented by measurement of serum thyroid hormones level. A battery of behavioral tasks, i. e. spontaneous activity, open field, weight lifting, balance bar, novel-object recognition, olfactory discrimination, Morris water maze, et al, was used to test mice's mood and memory. We then examined whether age and hypothyroid state affect the Calcium/ calmodulin-dependent protein kinaseⅡαsubunit (CaMKⅡα) in brain of the 2- and 15-month-old mice by the immunocytochemistry analysis and Western blot analysis. At last we examined whether age and hypothyroid state affect the thyroid hormone receptor(TR) mRNA in the brain of the 2- and 15-month-old mice byRT-PCR.Results The weight gains were slowed down by the hypothyroidism in the 2-month-old mice. The loss of weight was increased by the hypothyroidism in the 15-month-old mice. The hypothyroid mice had lower muscular strength. The adult-onset hypothyroidism induced the impairment of mood and memory. Age at onset of hypothyroidism influenced the severity of impaired mood and memory but did not influence the severity of impaired muscular strength. The 2-month-old hypothyroid had more severly depression than the 15-month-old hypothyroid mice. The 2-month-old hypothyroid mice had significantly impaired abilities in both the olfactory discrimination and the spatial cognitive tasks relative to the 2-month-old controls. The 8-month-old hypothyroid mice had only impaired ability in the spatial cognitive task relative to the same age controls. The 15-month-old hypothyroid mice retained these cognitive abilities relative to the same age controls. The CaMKⅡαprotein in the hippocampus of all mice were decreased by the hypothyroidism. The level of the change CaMKⅡαprotein by the hypothyroidism relative to that in the same aged mice is more significantly in the 2-month-old mice than in the 15-month-old mice. We did not completed the experiment of RT-PCR for the TR mRNA, we only observed there are TR mRNA expression in the cortex,hippocampus,and stritum in the 15-month-old mice.Conclusions Under the condition of the same serum thyroid hormones level and the same period of the PTU treatment, there is a reduced cerebral tissue responsiveness to hypothyroidism with age increasing in Kunming female mice.