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Thyroid hormone (TH) plays important roles in the developing brain. TH deficiency in early life leads to severe developmental impairment in the hippocampus. However, the mechanisms of TH action in the developing hippocampus are still largely unknown. In this study, we generated 3,5,3’-tri-iodo-l-thyronine (T3)-free neuronal supplement, based on the composition of neuronal supplement 21 (NS21), to examine the effect of TH in the developing hippocampus using primary cultured neurons. Effects of TH on neurons were compared between cultures in this T3-free culture medium (-T3 group) and a medium in which T3 was added (+T3 group). Morphometric analysis and RT-qPCR were performed on 7, 10, and 14 days in vitro (DIV). On 10 DIV, a decreased dendrite arborization in -T3 group was observed. Such difference was not observed on 7 and 14 DIV. Brain-derived neurotrophic factor (Bdnf) mRNA levels also decreased significantly in -T3 group on 10 DIV. We then confirmed protein levels of phosphorylated neurotrophic tyrosine kinase type 2 (NTRK2, TRKB), which is a receptor for BDNF, on 10 DIV by immunocytochemistry and Western blot analysis. Phosphorylated NTRK2 levels significantly decreased in -T3 group compared to +T3 group on 10 DIV. Considering the role of BDNF on neurodevelopment, we examined its involvement by adding BDNF on 8 and 9 DIV. Addition of 10 ng/ml BDNF recovered the suppressed dendrite arborization induced by T3 deficiency on 10 DIV. We show that the lack of TH induces a developmental delay in primary hippocampal neurons, likely caused through a decreased Bdnf expression. Thus, BDNF may play a role in TH-regulated dendritogenesis.

Elucidating the mechanisms underlying nurturing and neglect behaviors is meaningful but challenging. Recently, we found that CIN85-deficient mice had reduced pituitary hormone prolactin secretion during late pregnancy, and their pups later showed an inhibited nurturing behavior. To examine whether this phenomenon could be reproduced in normal mice and not just CIN85-deficient mice, we investigated the nurturing behavior of offspring born to mothers whose blood prolactin levels had been reduced by bromocriptine administration during late pregnancy. First, to determine when bromocriptine treatment should be started, we investigated the detailed changes in blood prolactin levels in late pregnancy in mice, resulting in the identification of the prepartum prolactin surge. Furthermore, prolactin receptors in the fetal hypothalamus were expressed to the same extent as in the adult hypothalamus. Treatment with bromocriptine decreased the plasma concentrations of prolactin to the basal range throughout late pregnancy. However, against expectations, the proportion of the resultant pups exhibiting nurturing behaviors as adults was as high as that in the mice without bromocriptine treatment. In conclusion, the elimination of prolactin secretion during late pregnancy alone does not induce neglect-like behavior in offspring, suggesting that CIN85-deficient mice appear to involve another factor due to CIN85 deficiency besides prolactin deficiency.