Hyperactivity, impaired learning on a vigilance task, and a differential response to methylphenidate in the TRbetaPV knock-in mouse.
BACKGROUND
The thyroid hormones (T3 and T4) play a critical role in brain development, and thyroid abnormalities have been linked to a variety of psychiatric and neuropsychological disorders. Among patients with the rare genetic syndrome resistance to thyroid hormone (RTH), 40-70% meet the diagnostic criteria for attention deficit-hyperactivity disorder (ADHD). RTH is caused by a mutation in the thyroid receptor beta (Thrb) gene that results in reduced binding of T3 to its receptor and elevated concentrations of T3, T4, and thyroid-stimulating hormone.


OBJECTIVE
We tested a knock-in (KI) mouse expressing a mutant TRbeta allele (TRbetaPV) for the behavioral features of ADHD and their response to methylphenidate (MPH).


METHODS
The locomotor activity of the TRbetaPV KI mice was measured in activity monitors over multiple sessions. Sustained attention and the effects of MPH on attention were assessed using a vigilance task.


RESULTS
The TRbetaPV KI mice are hyperactive and have learning deficits on a vigilance task. Doses of MPH that impair the vigilance performance of wild-type mice do not affect the performance of the TRbetaPV KI mice.


CONCLUSIONS
The TRbetaPV KI mice provide a tool for studying the underlying neural deficits that contribute to thyroid-related neurological disorders, hyperactivity, and altered responsiveness to MPH.
Siesser
William B
WB
Program in Neuroscience, Vanderbilt University, Nashville, TN 37232-0325, USA.
Cheng
Sheue-yann
SY
McDonald
Michael P
MP
D000483:Alleles; D000818:Animals; D001288:Attention / Q000187:drug effects*; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000523:psychology; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D004193:Discrimination Learning / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D008774:Methylphenidate / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D008957:Models, Genetic; D009043:Motor Activity / Q000187:drug effects*; D009154:Mutation; D037042:Thyroid Hormone Receptors beta / Q000235:genetics*
D000697:Central Nervous System Stimulants; D037042:Thyroid Hormone Receptors beta; D008774:Methylphenidate