Hyperactivity, impaired learning on a vigilance task, and a differential response to methylphenidate in the TRβPV knock-in mouse

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.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).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.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.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.