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Maternal Hypothyroxinemia Impairs Spatial Learning and Synaptic Nature and Function in the Offspring

Laboratorio de Biología Celular y Farmacología (M.C.O., A.G., L.A., R.L., V.N., C.A.R.), Departamento de Ciencias Biológicas, Universidad Andrés Bello, República 217 Santiago, Chile; Laboratorio de Neurotoxicología Ambiental (F.P.), Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Larrondo 1281, Coquimbo, Chile; Faculty of Medicine (G.A.), Department of Neuroscience, Universidad del País Vasco, Barrio Sarriena 48940, España; Millennium Nucleus on Immunology and Immunotherapy (P.A.G., S.M.B., A.M.K.), Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas (P.A.G.), Departamento de Reumatología (A.M.K.), Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Instituto de Biofísica Carlos Chagas Filho of Federal University of Rio de Janeiro (M.P., D.R.), 21941-590 Rio de Janeiro, Brazil; Instituto de Ciencias Biomédicas (S.M.), Facultad de Medicina Universidad de Chile, 1027 Santiago, Chile; Department of Pathology (E.E.), Albert Einstein College of Medicine, Bronx, New York 10461; and Centro de Neurociencias de Valparaiso (D.N.), Facultad de Ciencias, Universidad de Valparaíso, Errázuriz 1834, Valparaíso, Chile

Address all correspondence and requests for reprints to: Dr. Claudia Riedel, Laboratorio de Biología Celular y Farmacología, Departamento de Ciencias Biológicas, Universidad Nacional Andrés Bello, República 217 Santiago, Chile. E-mail: riedel{at}unab.cl.

Neurological deficits in the offspring caused by human maternal hypothyroxinemia are thought to be irreversible. To understand the mechanism responsible for these neurological alterations, we induced maternal hypothyroxinemia in pregnant rats. Behavior and synapse function were evaluated in the offspring of thyroid hormone-deficient rats. Our data indicate that, when compared with controls, hypothyroxinemic mothers bear litters that, in adulthood, show prolonged latencies during the learning process in the water maze test. Impaired learning capacity caused by hypothyroxinemia was consistent with cellular and molecular alterations, including: 1) lack of increase of phosphorylated c-fos on the second day of the water maze test; 2) impaired induction of long-term potentiation in response to theta-burst stimulation to the Schaffer collateral pathway in the area 1 of the hippocampus Ammon’s horn stratum radiatum, despite normal responses for input/output experiments; 3) increase of postsynaptic density protein 95 (PSD-95), N-methyl-D-aspartic acid receptor subunit 1, and tyrosine receptor kinase B levels in brain extracts; and 4) significant increase of PSD-95 at the PSDs and failure of this molecule to colocalize with N-methyl-D-aspartic acid receptor subunit 1, as it was shown by control rats. Our findings suggest that maternal hypothyroxinemia is a harmful condition for the offspring that can affect key molecular components for synaptic function and spatial learning.

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