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Developmental Thyroid Hormone Insufficiency Reduces Expression of Brain-Derived Neurotrophic Factor (BDNF) in Adults But Not in Neonates
Lasley, S. M. AND M. E. GILBERT. Developmental Thyroid Hormone Insufficiency Reduces Expression of Brain-Derived Neurotrophic Factor (BDNF) in Adults But Not in Neonates. NEUROTOXICOLOGY AND TERATOLOGY. Elsevier Science Ltd, New York, NY, 33(4):464-472, (2011).
Thyroid hormone regulates gene expression during critical periods of development in a number of organ systems, but most particularly the brain. Brain derived neurotrophic factor (BDNF) is a protein belonging to the neurotrophin family of growth factors. The activity of this neurotrophin is central to many developmental and physiological aspects of eNS function, ranging from neuronal differentiation and survival to synaptogenesis and activity-dependent forms of synaptic plasticity and learning. BDNF has been implicated in neurodevelopmental disorders, neurodegenerative disease, psychiatric disorders, and depression. Given the well documented role of BDNF on brain during development and in adult brain function and plasticity, we propose that alterations in BDNF may underlie some of the persistent neurological impairments associated with developmental hypothyroidism
Brain-derived neurotrophic factor (BDNF) is a neurotrophin critical for many developmental and physiological aspects of CNS function. Severe hypothyroidism in the early neonatal period results in developmental and cognitive impairments and reductions in mRNA and protein expression of BDNF in a number of brain regions. The present study examined the impact of modest levels of developmental thyroid hormone insufficiency on BDNF protein expression in the hippocampus, cortex and cerebellum in the neonatal and adult offspring of rat dams treated throughout pregnancy and lactation. Graded levels of hormone insufficiency were induced by adding propylthiouracil (PTU, 0, 1,2, 3 and 10 ppm) to the drinking water of pregnant dams from early gestation (gestational day 6) until weaning of the pups. Pups were sacrificed on postnatal days (PN) 14 and 21, and ~PN100, and trunk blood collected for thyroid hormone analysis. Hippocampus, cortex, and cerebellum were separated from dissected brains and assessed for BDNF protein. Dose-dependent reductions in serum hormones in dams and pups were produced by PTU. Consistent with previous findings, age and regional differences in BDNF concentrations were observed. However, no differences in BDNF expression were detected in the preweanling animals as a function of PTU exposure; dose-dependent alterations emerged in adulthood despite the return of thyroid hormone levels to control values. Males were more affected by PTU than females, BDNF levels in hippocampus and cortex were altered but not those in cerebellum, and biphasic dose-response functions were detected in both sexes. These findings indicate that BDNF may mediate some of the adverse effects accompanying developmental thyroid hormone insufficiency, and reflect the potential for delayed impact of modest reductions in thyroid hormones during critical periods of brain development on a protein important for normal synaptic function.