Aberrant Monoaminergic System in Thyroid Hormone Receptor-β Deficient Mice as a Model of Attention-Deficit/Hyperactivity Disorder

Background: Thyroid hormone receptors are divided into 2 functional types: TR alpha and TR beta. Thyroid hormone receptors play pivotal roles in the developing brain, and disruption of thyroid hormone receptors can produce permanent behavioral abnormality in animal models and humans. Methods: Here we examined behavioral changes, regional monoamine metabolism, and expression of epigenetic modulatory proteins, including acetylated histone H3 and histone deacetylase, in the developing brain of TR alpha-disrupted (TR alpha(0/0)) and TR beta-deficient (TR beta(-/-)) mice. Tissue concentrations of dopamine, serotonin (5-hydroxytryptamine) and their metabolites in the mesocorticolimbic pathway were measured. Results: TR beta(-/-) mice, a model of attention-deficit/hyperactivity disorder, showed significantly high exploratory activity and reduced habituation, whereas TR alpha(0/0) mice showed normal exploratory activity. The biochemical profiles of dopamine and 5-hydroxytryptamine showed significantly low dopamine metabolic rates in the caudate putamen and nucleus accumbens and overall low 5-hydroxytryptamine metabolic rates in TR beta(-/-) mice, but not in TR alpha(0/0) mice. Furthermore, the expression of acetylated histone H3 was low in the dorsal raphe of TR beta(-/-) mice, and histone deacetylase 2/3 proteins were widely increased in the mesolimbic system. Conclusions: These findings suggest that TR beta deficiency causes dysfunction of the monoaminergic system, accompanied by epigenetic disruption during the brain maturation process.