Identity Crisis: Parvalbumin Expressing GABA Neurons Disappear Under Conditions of Iodine Deficiency and Perchlorate Exposure
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Background and Purpose:
Thyroid Hormones (TH) production can be altered by Endocrine Disrupting Chemicals (EDCs). TH are essential to proper development, including that of the brain. TH are key to the differentiation of inhibitory interneurons including those expressing the calcium-binding protein, Parvalbumin (Pvalb). Recent studies of genetically modified mouse models of TH receptors, transporters, and metabolizing enzymes have revealed Pvalb-expressing neurons are sensitive to perturbations of the thyroid axis. We sought to create a more environmentally and physiologically relevant model to determine if thyroid axis perturbations, induced by Iodine deficiency (ID) or per[KC1] chlorate exposure, would alter Pvalb expression in the developing rat brain.
Methods:
Female LE rats were maintained on a diet of either sufficient or insufficient iodine for at least 4 weeks before breeding. On gestational day (GD) 6, sperm-positive females were then exposed to either 0 or 300 ppm perchlorate through their drinking water. Dams and pups were euthanized on postnatal days 14 and 21, respectively, and serum was collected for TH analysis. Brains collected from male and female pups on PN14 (6-8 litters/treatment gp) were prepared for Pvalb-immunohistochemistry. At PN104-117 male and female offspring were subjected to prepulse inhibition of the acoustic startle response.
Results:
Compared to the controls, perchlorate exposure alone reduced serum T4 by 60% and ID alone reduced serum T4 by 40% in the dams without any significant effects in the offspring. However, when combined, ID and perchlorate exposure reduced serum T4 by ~75% in dams, a similar decrease was mirrored in the pups. Cell counts conducted in somatosensory, cingulate, and auditory cortices revealed no difference from the controls in the number of Pvalb-expressing neurons in either the ID or perchlorate exposed groups. When exposures were combined however, ~50% reduction was observed in all three cortical regions. Examination of Pvalb-expressing neurons in the superior blade of the dentate gyrus of the hippocampus also followed a similar pattern, with no difference from control in the individually treated groups, but ~50% reduction in the number of Pvalb-expressing cells with co-exposure. No sex differences were detected in any of the brain regions assessed. Increases in startle amplitude were seen in male offspring exposed to perchlorate, and male and female offspring in the co-exposure group. Similarly, reductions in prepulse inhibition were evident in males and females in the co-exposed group.
Conclusions:
These data support the conclusion that Pvalb is a sensitive marker for TH disruption induced by EDCs. Pvalb-expressing interneurons are crucial to the formation of neural networks and their disruption during development may contribute to neurological impairments associated with TH insufficiency. This study highlights the importance of studying the impact of EDCs under other environmentally relevant conditions, such as a ID. Individuals can be affected by a variety of environmental factors, studying healthy animals in ideal environments may obscure neurodevelopmental consequences, such as the deficits found when chemical and non-chemical stressors are combined. Does not reflect EPA policy.