Abstract
Maternal subclinical hypothyroidism (SCH) during pregnancy can adversely affect the neurodevelopment of the offspring. The balance of nerve growth factor (NGF)-related tropomyosin receptor kinase A/p75 neurotrophin receptor (TrkA/p75NTR) signaling in the hippocampus is important in brain development, and whether it affects cognitive function in maternal SCH’s offspring is not clear. In this study, we found that compared with the control (CON) group, expression of proliferation-related proteins [NGF, p-TrkA, phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2) and phospho-cAMP response element-binding protein (p-CREB)] decreased in the hippocampus of the offspring in the SCH group, overt hypothyroidism (OHT) group, and the group with levothyroxine (L-T4) treatment for SCH from gestational day 17 (E17). In contrast, expression of apoptosis-related proteins [pro-NGF, p75NTR, phospho-C-Jun N-terminal kinase (p-JNK), p53, Bax and cleaved caspase-3] was increased. The two groups with treatment with L-T4 for SCH from E10 and E13, respectively, showed no significant difference compared with the CON group. L-T4 treatment enhanced relative expression of NGF by increasing NGF/proNGF ratio in offspring from maternal SCH rats. In conclusion, L-T4 treatment for SCH from early pregnancy dramatically ameliorated cognitive impairment via TrkA/p75NTR signaling, which involved activation of the neuronal proliferation and inhibition of neuronal apoptosis in SCH rats’ offspring.
Highlights
Thyroid hormones (THs) are essential for brain development and have a critical role in fetal brain development [1, 2]
We have reported that the expression of brainderived neurotrophic factor (BDNF) and its downstream molecules are altered in the offspring of maternal rats with subclinical hypothyroidism (SCH) [11, 12]
These results indicated that treatment with L-T4 was successful and additional L-T4 supplements recovered normal thyroid status in maternal rats
Summary
Thyroid hormones (THs) are essential for brain development and have a critical role in fetal brain development [1, 2]. NGF plays a critical role in neurodevelopment by activating the TrkA signaling pathway and inhibiting the p75NTR signaling pathway [14, 19,20,21,22]. Reduction of NGF in the cerebral cortex and cerebellum has been detected in the offspring of rats with perinatal hypothyroidism. This leads to inhibition of the TrkA signaling pathway, activation of the p75NTR signaling pathway, and imbalance in the TrkA/p75NTR signaling pathway [23, 24]. Whether an imbalance of the TrkA/p75NTR signaling pathway is found in hippocampal development in offspring of SCH rats has not been clarified
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