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Submitted on February 9, 2006
Accepted on September 20, 2006
Neurotoxicology Division, US Environmental Protection Agency, Research Triangle Park, NC, USA; Department of Psychology, University of North Carolina, NC, USA; National Research Council, Washington, DC, USA; Center for Neural Recovery and Rehabilitation Research, Helen Hayes Hospital, West Haverstraw, NY, USA
* To whom correspondence should be addressed. E-mail: gilbert.mary{at}epa.gov.
Thyroid hormones are necessary for brain development. GABAergic interneurons comprise the bulk of local inhibitory circuitry in brain, many of which contain the calcium binding protein, parvalbumin (PV). A previous report has indicated that severe postnatal hypothyroidism reduces PV immunoreactivity (PV-IR) in rat neocortex. We examined PV-IR and GABA-mediated synaptic inhibition in the hippocampus of rats deprived of thyroid hormone from gestational day 6 until weaning on postnatal day (PN) 30. Pregnant dams were exposed to propylthiouracil (PTU, 0, 3, 10ppm) via the drinking water which decreased maternal serum T4 by 
50%-75% and increased TSH. At weaning, T4 was reduced by 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 PN21, 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.
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