title: Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats.
abstract: Severe thyroid hormone (TH) deficiency during critical phases of brain development results in irreversible neurological and cognitive impairments. The mechanisms accounting for this are likely multifactorial, and are not fully understood. Here we pursue the possibility that one important element is that TH affects basal and activity-dependent neurotrophin expression in brain regions important for neural processing. Graded exposure to propylthiouracil (PTU) during development produced dose-dependent reductions in mRNA expression of nerve growth factor (Ngf) in whole hippocampus of neonates. These changes in basal expression persisted to adulthood despite the return to euthyroid conditions in blood. In contrast to small PTU-induced reductions in basal expression of several genes, developmental PTU treatment dramatically reduced the activity-dependent expression of neurotrophins and related genes (Bdnft, Bdnfiv, Arc, and Klf9) in adulthood and was accompanied by deficits in hippocampal-based learning. These data demonstrate that mild TH insufficiency during development not only reduces expression of important neurotrophins that persists into adulthood but also severely restricts the activity-dependent induction of these genes. Considering the importance of these neurotrophins for sculpting the structural and functional synaptic architecture in the developing and the mature brain, it is likely that TH-mediated deficits in these plasticity mechanisms contribute to the cognitive deficiencies that accompany developmental TH compromise.
authors.affiliation: Toxicity Assessment Division (M.E.G., C.W.), National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27709; Departamento de Fisiología "Mauricio Russek" (K.S.-H.), Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico 07738.
authors.forename: M E
authors.initials: ME
authors.lastname: Gilbert
authors.affiliation: Toxicity Assessment Division (M.E.G., C.W.), National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27709; Departamento de Fisiología "Mauricio Russek" (K.S.-H.), Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico 07738.
authors.forename: K
authors.initials: K
authors.lastname: Sanchez-Huerta
authors.affiliation: Toxicity Assessment Division (M.E.G., C.W.), National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27709; Departamento de Fisiología "Mauricio Russek" (K.S.-H.), Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico 07738.
authors.forename: C
authors.initials: C
authors.lastname: Wood
mesh_terms: D000818:Animals; D013956:Antithyroid Agents / Q000633:toxicity; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D003409:Congenital Hypothyroidism / Q000139:chemically induced / Q000196:embryology* / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005239:Fear; D005260:Female; D006624:Hippocampus / Q000196:embryology* / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D020932:Nerve Growth Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D020933:Neurotrophin 3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000378:metabolism*; D011441:Propylthiouracil / Q000633:toxicity; D051381:Rats; D020318:Rats, Long-Evans; D012720:Severity of Illness Index; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013974:Thyroxine / Q000172:deficiency / Q000187:drug effects / Q000378:metabolism; D014284:Triiodothyronine / Q000172:deficiency / Q000187:drug effects / Q000378:metabolism
chemical_list: D013956:Antithyroid Agents; D019208:Brain-Derived Neurotrophic Factor; D003598:Cytoskeletal Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; C092069:activity regulated cytoskeletal-associated protein; D014284:Triiodothyronine; C077017:Klf9 protein, rat; D011441:Propylthiouracil; D020932:Nerve Growth Factor; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D013974:Thyroxine