Thyroid Hormone Insufficiency during Brain Development Reduces Parvalbumin Immunoreactivity and Inhibitory Function in the Hippocampus

• Published in: Endocrinology (Philadelphia) 2007-01, Vol.148 (1), p.92-102
• Main Authors: Gilbert, M. E, Sui, L, Walker, M. J, Anderson, W, Thomas, S, Smoller, S. N, Schon, J. P, Phani, S, Goodman, J. H
• Format: Article
• Language: English
• Subjects: Age Factors; Animals; Antithyroid Agents - pharmacology; Biological and medical sciences; Brain; Butyric acid; Calcium-binding protein; Cerebral cortex; Circuits; Dentate gyrus; Dentate Gyrus - embryology; Dentate Gyrus - metabolism; Drinking water; Female; Fundamental and applied biological sciences. Psychology; Genetic crosses; Hippocampus; Hormones; Hypothyroidism; Hypothyroidism - chemically induced; Hypothyroidism - metabolism; Immunohistochemistry; Immunoreactivity; In vivo methods and tests; Interneurons; Interneurons - metabolism; Neocortex; Neocortex - embryology; Neocortex - metabolism; Neural Inhibition - physiology; Offspring; Paired-pulse depression; Parvalbumin; Parvalbumins - metabolism; Postpartum period; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Propylthiouracil - pharmacology; Rats; Rats, Long-Evans; Synaptic depression; Synaptic Transmission - physiology; Thyroid; Thyroid gland; Thyroid hormones; Thyroid Hormones - deficiency; Thyroid Hormones - pharmacology; Thyroid-stimulating hormone; Thyroxine; Vertebrates: endocrinology; Weaning; γ-Aminobutyric acid
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2006-0164

Thyroid hormones are necessary for brain development. γ-Amino-butyric acid (GABA)ergic interneurons comprise the bulk of local inhibitory circuitry in brain, many of which contain the calcium binding protein, parvalbumin (PV). A previous report indicated that severe postnatal hypothyroidism reduces PV immunoreactivity (IR) in rat neocortex. We examined PV-IR and GABA-mediated synaptic inhibition in the hippocampus of rats deprived of thyroid hormone from gestational d 6 until weaning on postnatal d 30. Pregnant dams were exposed to propylthiouracil (0, 3, 10 ppm) via the drinking water, which decreased maternal serum T4 by approximately 50–75% and increased TSH. At weaning, T4 was reduced by approximately 70% in offspring in the low-dose group and fell below detectable levels in high-dose animals. PV-IR was diminished in the hippocampus and neocortex of offspring killed on postnatal d 21, an effect that could be reversed by postnatal administration of T4. Dose-dependent decreases in the density of PV-IR neurons were observed in neocortex and hippocampus, with the dentate gyrus showing the most severe reductions (50–75% below control counts). Altered staining persisted to adulthood despite the return of thyroid hormones to control levels. Developmental cross-fostering and adult-onset deprivation studies revealed that early postnatal hormone insufficiency was required for an alteration in PV-IR. Synaptic inhibition of the perforant path-dentate gyrus synapse evaluated in adult offspring, in vivo, revealed dose-dependent reductions in paired pulse depression indicative of a suppression of GABA-mediated inhibition. These data demonstrate that moderate degrees of thyroid hormone insufficiency during the early postnatal period permanently alters interneuron expression of PV and compromises inhibitory function in the hippocampus.