Developmental Hypothyroidism Results in a Brain Region-Specific Reduction in Insulin-like Growth Factor 1 Positive Cells

Presentation Number: SAT 424
Date of Presentation: April 1st, 2017

Cari Graber-Feesl*1, Shelby Kline2 and David S Sharlin3
1Minnesota State University, Manakto, Mankato, MN, 2Minnesota State University, Mankato, 3Minnesota State University Mankato, Mankato, MN


Insufficient thyroid hormone (TH) during development results in permanent neurological deficits. These deficits are the result of perturbed TH-mediated brain development. Interestingly, insufficient insulin-like growth factor 1 (Igf-1) during development results in neurological deficits that are similar to those reported for developmental hypothyroidism. This observation suggests that deficits associated with low TH during development may be the result of altered Igf-1 expression in the developing brain. To test this, timed-pregnant mice were treated with thyroid gland inhibitors from gestational day 16 (GD16) until postnatal day 21 (P21) to induce a hypothyroid state. A parallel set of untreated timed-pregnant mice were used as controls. Brains from exposed and control pups were collected at P7, P14, P21, and P42 and processed for detecting Igf-1 mRNA by in situ hybridization or quantitative real-time PCR. Additionally, trunk blood was collected to measure serum thyroxin (T4) and Igf-1 by ELISA. Significant reductions in serum T4 and Igf-1 at P14 and P21 were observed. No change in serum T4 or Igf-1 were observed at P7 or at P42 following goitrogen withdrawal at P21. Furthermore, serum T4 and Igf-1 were positively correlated across all ages investigated. In situ hybridization revealed the presence of Igf-1 positive cells in well-known TH sensitive brain regions including the motor cortex, hippocampus, and cerebellum. Quantification of Igf-1 positive cells demonstrated a significant reduction in hypothyroid pups compared to controls in the cortex at all ages, but not in the hippocampus or cerebellum. Considering serum T4 and Igf-1 are normalized by P42, this result indicates that developmental hypothyroidism results in a spatially specific permanent reduction in brain Igf-1 positive cells. This reduction in Igf-1 synthesizing cells would result in reduced local levels of brain Igf-1. These findings identify a novel, previously unconsidered, mechanism by which thyroid hormone insufficiency during development results in neurological deficits.


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