Int J Neuropsychopharmacol. 2015 Jan 22;18(7):pyv004.

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

Ookubo M1, Sadamatsu M1, Yoshimura A1, Suzuki S1, Kato N1, Kojima H1, Yamada N1, Kanai H2.
  • 1Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan (Drs Ookubo, Yoshimura, Yamada, and Kanai); Department of Psychiatry, Minakuchi Hospital, Shiga, Japan (Dr Ookubo); Department of Psychology and Psychiatry, Human Sciences, Kinjo Gakuin University, Aich, Japan (Dr Sadamatsu); Department of Thyroid and Endocrinology, Fukushima Medical University, Fukushima, Japan (Dr Suzuki); Department of Psychiatry, Showa University School of Medicine, Tokyo, Japan (Dr Kato); Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Shiga, Japan (Dr. Kojima); Department of Psychiatry, Japanese Red Cross Society Nagahama Hospital, Shiga, Japan (Dr. Kanai).
  • 2Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan (Drs Ookubo, Yoshimura, Yamada, and Kanai); Department of Psychiatry, Minakuchi Hospital, Shiga, Japan (Dr Ookubo); Department of Psychology and Psychiatry, Human Sciences, Kinjo Gakuin University, Aich, Japan (Dr Sadamatsu); Department of Thyroid and Endocrinology, Fukushima Medical University, Fukushima, Japan (Dr Suzuki); Department of Psychiatry, Showa University School of Medicine, Tokyo, Japan (Dr Kato); Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Shiga, Japan (Dr. Kojima); Department of Psychiatry, Japanese Red Cross Society Nagahama Hospital, Shiga, Japan (Dr. Kanai). h-kanai@nagahama.jrc.or.jp.

 

Abstract

BACKGROUND: Thyroid hormone receptors are divided into 2 functional types: TRα and TRβ. 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 behavioralchanges, regional monoamine metabolism, and expression of epigenetic modulatory proteins, including acetylated histone H3 and histone deacetylase, in the developing brain of TRα-disrupted (TRα (0/0) ) and TRβ-deficient (TRβ (-/-) ) mice. Tissue concentrations of dopamine, serotonin (5-hydroxytryptamine) and their metabolites in the mesocorticolimbic pathway were measured.

RESULTS: TRβ (-/-) mice, a model of attention-deficit/hyperactivity disorder, showed significantly high exploratory activity and reduced habituation, whereas TRα (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 TRβ (-/-) mice, but not in TRα (0/0) mice. Furthermore, the expression of acetylated histone H3 was low in the dorsal raphe of TRβ (-/-) mice, and histone deacetylase 2/3 proteins were widely increased in the mesolimbic system.

CONCLUSIONS:These findings suggest that TRβ deficiency causes dysfunction of the monoaminergic system, accompanied by epigenetic disruption during the brain maturation process.

KEYWORDS:

ADHD; dopamine; histone deacetylase; reward system; serotonin

PMID: 25612897

 

Supplement:

 

FIG1

Male and female TRβ−/− mice similarly showed hyperactivity compared to wild type mice. A figure displays average distances of ambulation every 45-sec bin during 3 min in the open field test. Asterisks indicate significant differences from WT mice (*p < 0.05, **p < 0.01 , ***p < 0.005).

 

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