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THYROID HORMONE INSUFFICIENCY DURING BRAIN DEVELOPMENT REDUCES PARVALBUMIN IMMUNOREACTIVITY AND INHIBITORY FUNCTION IN THE HIPPOCAMPUS.
Citation:
GILBERT, M. E., L. SUI, M. J. WALKER, W. L. ANDERSON, S. THOMAS, S. N. SMOLLER, J. P. SCHON, S. PHANI, AND J. H. GOODMAN. THYROID HORMONE INSUFFICIENCY DURING BRAIN DEVELOPMENT REDUCES PARVALBUMIN IMMUNOREACTIVITY AND INHIBITORY FUNCTION IN THE HIPPOCAMPUS. JOURNAL OF ENDOCRINOLOGY. Society for Endocrinology, Bristol, 148(1):92-102, (2007).
Impact/Purpose:
To help evaluate the risk of exposure of the developing brain to chemicals with the potential to disrupt thyroid hormone homeostasis
Description:
The EPA must evaluate the risk of exposure of the developing brain to chemicals with the potential to disrupt thyroid hormone homeostasis. The existing literature identifies morphological and neurochemical indices of severe neonatal hypothyroidism in the early postnatal period in classic animal models of hypothyroidism. We have recently described functional perturbations in excitatory synaptic transmission in the hippocampus of adult offspring of hormone compromised dams using the prototypic thyroid hormone disruptor, propylthiouracil. The current manuscript identifies an additional deficiency in inhibitory synaptic transmission in animals experiencing insufficient hormonal levels during development. The loss of inhibitory function is coupled with a reduction in the expression of a calcium-binding protein, parvalbumin, that is selectively localized in inhibitory neurons of the hippocampus and cortex. These observations add to a series of papers that establishes that perturbations in synaptic function exist in a brain region which is critically involved in learning and memory. Dose-dependent reductions in parvalbumim immunoreactivity were present in young animals hormone deficient at the time of assessment. Both qualitative and quantitative stereological counts of cell number and fiber staining were observed. Although some recovery of staining density was evident in adulthood, persistent reductions remained despite return of thyroid hormones to control levels. These alterations in immunoreactivity were coupled with decreases in inhibitory transmission in the dentate gyrus of the hippocampus. Expression of parvalbumin in brain begins on postnatal 8 in developing rat pups. Animals experiencing hypothyroidism as adults or animals whose hypothyroidism was limited to the prenatal period did not demonstrate alterations in parvalbumin immunostaining indicating a critical window of hormonal insufficiency for this effect exists during the early postnatal period. Ongoing experiments using short-term hormone replacement therapy during different windows of postnatal brain development will further refine the critical window of exposure. These data are important for three main reasons: 1) They represent one of the few dose-response characterizations of functional deficits in hippocampal transmission in an intact preparation following developmental hormone insufficiency. 2) They show correlative dose-dependent impairments in brain anatomy and function 3) They reveal impairments following moderate degrees of thyroid hormone reductions during development that persist despite full recovery of hormonal status at the time of assessment. These in vivo observations in synaptic function provide a critical foundation for biologically-based dose response modelling, offer the opportunity to correlate functional deficits in synaptic transmission to anatomical alterations, and serve to better refine cellular substrates for further exploration.