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.

The dentate granule cell (DG) layer of the hippocampal formation has the distinctive property of ongoing neurogenesis that continues throughout adult life. Although the function of these newly generated neurons and the mechanisms that control their birth are unknown, age, activity, diet and psychosocial stress have all been demonstrated to regulate this type of neurogenesis. Little information on the impact of environmental insults on this process has appeared to date. Developmental lead (Pb) exposure has been well documented to impair cognitive function in children and animals and reduce activity-dependent synaptic plasticity in the hippocampus of rodents. Therefore, we examined the effects of this classic environmental neurotoxicant on hippocampal-dependent learning and adult neurogenesis in the hippocampus. Pregnant rats were exposed to a low level of Pb-acetate (0.2%) via the drinking water from late gestation (GD 16) until weaning on postnatal day 21 (PN 21). At weaning, half of the Pb-exposed animals were weaned to control drinking water and the remainder were maintained on Pb water until termination of the study. Animals were paired- housed and on PN 75 were administered a series of injections of a thymidine analog bromodeoxyuridine (BrdU), a marker of DNA synthesis that labels proliferating cells and their progeny. At 12-h intervals for 12 days, rats received an ip injection of BrdU (50 mg/kg). Subjects were sacrificed and perfused 24 h and 28 days after the last injection. Spatial learning was assessed in an independent group of animals beginning on PN 110 using a Morris water maze. No Pb-induced impairments were evident in water maze learning. Immunohistochemistry for the detection of BrdU-labeled cells was performed on 40-μm coronal sections throughout the hippocampus. Continuous exposure to Pb (Life) reduced the total number of BrdU-positive cells at 28 days without affecting the total number of labeled cells evident 24 h after the last injection. No differences in the number of progenitor cells labeled or surviving were seen between control and treated animals whose Pb exposure was terminated at weaning. Double labeling with BrdU and the glial specific marker, glial acidic fibrillary protein (GFAP) indicated that the bulk of the surviving cells were of a neuronal rather than a glial phenotype. These data reveal that chronic low-level Pb exposure reduces the capacity for neurogenesis in the adult hippocampus. Despite deficits in synaptic plasticity previously reported from our laboratory (e.g., Gilbert, M. E., Mack, C. M., and Lusley, S. M. Brain Res. 1996; 736, 118–124), and now structural plasticity, no significant impact on spatial learning was detected.

Synthetic chemicals with endocrine disrupting properties are pervasive in the environment and are present in the bodies of humans and wildlife. As thyroid hormones (THs) control normal brain development, and maternal hypothyroxinemia is associated with neurological impairments in children, chemicals that interfere with TH signaling are of considerable concern for children’s health. However, identifying thyroid-disrupting chemicals (TDCs) in vivo is largely based on measuring serum tetraiodothyronine in rats, which may be inadequate to assess TDCs with disparate mechanisms of action and insufficient to evaluate the potential neurotoxicity of TDCs. In this review 2 neurodevelopmental processes that are dependent on TH action are highlighted, neuronal migration and maturation of gamma amino butyric acid-ergic interneurons. We discuss how interruption of these processes by TDCs may contribute to abnormal brain circuitry following developmental TH insufficiency. Finally, we identify issues in evaluating the developmental neurotoxicity of TDCs and the strengths and limitations of current approaches designed to regulate them. It is clear that an enhanced understanding of how THs affect brain development will lead to refined toxicity testing, reducing uncertainty and improving our ability to protect children’s health.