The Effects Of Hypothyroidism On The Development Of Cerebral Glial Cells And Associated Behavior

Objective:Congenital hypothyroidism (CH) is a common disease in children. CH if not diagnosed early or left untreated, may cause delayed physical development and mental retardation. This study is designed to determine the consequences of hypothyroidism on the development of cereberal glial cells and associated behavior.Methods:Sixty C57BL/6J mice (40 female and 20 male) were purchased. The pregnant dams were treated with 0.03% methylmercaptoimidazole (MMI) in drinking water since the 10th gestational day. Then, after birth, the treatment continued until the day of killing (persistent hypothyroidism group, H) or stopped at postnatal day 7 (early hypothyroidism group, EH). Both mothers and their litters in the control group (group CN) received pure water.Maternal thyroid hormone concentrations were measured at the end of lactation. Body weights and serum thyroid hormone concentrations of litters were measured during development. The animals were killed at P1, P7, P14, P21 and P60. We studied the status of cerebral 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNPase, marker of oligodendrocyte) and Glial fibrillary acidic protein (GFAP, marker of astrocyte) and their encoding mRNA levels. Moreover, we studied the cerebral gene expression level of Angiotensin type 1 and type 2 receptors (AT1,AT2 receptor). Novel object recognition task was performed at P50 to test visual recognition memory.Results:1,Maternal thyroid hormones alterations:MMI significantly reduced maternal thyroid hormone (TT3,FT3,TT4,FT4) of group H, but there was no significant difference between group EH and group CN.2,Litters' thyroid hormones alterations:â‘ The serum T3 concentrations of hypothyroid mouse (group H) were significantly reduced and were reversed in early hypothyroid mouse (group EH).â‘¡The serum T4 concentrations of hypothyroid mouse (group H) were significantly reduced and were reversed more slowly than T3 in early hypothyroid mouse (group EH).3,The hypothyroid mouse had lower body weights than the controls, and can not be reversed even if the thyroid function has recovered.3,Effects of hypothyroidism on oligodendrocyte development:Developmental hypothyroidism induced a significant reduction in the CNPase mRNA and protein concentration from P7 to P14, and these effects were reversed after the recover of thyroid hormones.4,Effects of hypothyroidism on astrocyte development:Developmental hypothyroidism disturbed GFAP mRNA expression and reduced the GFAP protein concentrations from P7 to P60, and these effects were reversed after the recover of serum thyroid hormones.5,Developmental hypothyroidism disturbed the mRNA expression of AT1 receptor, and increased the mRNA level of AT2 receptor.6,Compared with the controls, hypothyroid mouse showed behavioral deficits in visual recognition memory (novel object recognition task) at P50, and can not be reversed in group EH.Conclusion:These studies showed that hypothyroidism can delay and disturb the development of oligodendrocytes and astrocytes. Moreover, developmental hypothyroidism can significantly alter the physical and behavioral outcomes in pups. The abnormal development of astrocytes may due to the alterations of cerebral AT1 and AT2 mRNA levels. These biological effects may partly be responsible for the abnormal behavioral outcomes.