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

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Abstract

Rationale

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 β (Thrb) gene that results in reduced binding of T3 to its receptor and elevated concentrations of T3, T4, and thyroid-stimulating hormone.

Objectives

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

Methods

The locomotor activity of the TRβPV 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 TRβPV 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 TRβPV KI mice.

Conclusions

The TRβPV KI mice provide a tool for studying the underlying neural deficits that contribute to thyroid-related neurological disorders, hyperactivity, and altered responsiveness to MPH.

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Acknowledgements

The authors wish to thank Isha Dhringa, Andrew Misfeldt, and Jiali Zhao for technical assistance, Nicole Schramm for comments on the manuscript, and Warren Lambert for advice on statistical analysis. These experiments comply with the current laws of the country in which they were performed and with the principles of laboratory animal care.

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Authors and Affiliations

  1. Program in Neuroscience, Vanderbilt University, Nashville, TN, 37232-0325, USA

    William B. Siesser & Michael P. McDonald

  2. Gene Regulation Section, Laboratory of Molecular Biology, National Cancer Institute, Bethesda, MD, 20892, USA

    Sheue-yann Cheng

  3. Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232-0325, USA

    Michael P. McDonald

  4. John F. Kennedy Center for Research in Human Development, Vanderbilt University, Nashville, TN, 37232-0325, USA

    Michael P. McDonald

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  1. William B. Siesser
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  2. Sheue-yann Cheng
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Correspondence to Michael P. McDonald.

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Siesser, W.B., Cheng, Sy. & McDonald, M.P. Hyperactivity, impaired learning on a vigilance task, and a differential response to methylphenidate in the TRβPV knock-in mouse. Psychopharmacology 181, 653–663 (2005). https://doi.org/10.1007/s00213-005-0024-5

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  • DOI: https://doi.org/10.1007/s00213-005-0024-5

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