Behavioral inhibition and impaired spatial learning and memory in hypothyroid mice lacking thyroid hormone receptor α

Thyroid hormone insufficiency leads to impaired neurogenesis, behavioral alterations and cognitive deficits. Thyroid hormone receptors, expressed in brain regions involved in these behaviors, mediate the effects of thyroid hormone deficiency or excess. To determine the contribution of thyroid hormone receptor alpha (TR alpha) in these behaviors, we examined the behavior of euthyroid as well as hypo- and hyperthyroid mice lacking all isoforms of the TR alpha (TR alpha(o/o)). The hypothyroxinemic TR alpha(o/o) mice demonstrated behavioral inhibition, manifested in decreased activity and increased anxiety/fear in the open field test (OFT) and increased immobility in the forced swim test (FST) compared to C57BL/6J mice. TR alpha(o/o) mice also showed learning and recall impairments in the Morris water maze (MWM), which were exaggerated by hypothyroidism in TR alpha(o/o) mice. These impairments were concurrent with increased thigmotaxis, suggesting an increased anxiety-like state of the TR alpha(o/o) mice in the MWM. Expression of genes, known to be involved in processes modulating learning and memory, such as glucocorticoid receptor (GR), growth-associated protein 43 (GAP-43) and neurogranin (RC3), were significantly decreased in the hippocampus of TR alpha(o/o) mice. GR expression was also decreased in the frontal cortex and amygdala of TR alpha(o/o) mice, indicating that expression of GR is regulated, probably developmentally, by one or more isoforms of TR alpha in the mouse brain. Taken together these data demonstrate behavioral alterations in the TR alpha(o/o) mice, indicating the functional role of TR alpha, and a delicate interaction between TR alpha and TR beta-regulated genes in these behaviors. Thyrcid hormone-regulated genes potentially responsible for the learning deficit found in TR alpha(o/o) mice include GR, RC3 and GAP-43. (c) 2006 Elsevier B.V. All rights reserved.