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RESEARCH PAPER

Anxiety, memory impairment, and locomotor dysfunction caused by a mutant thyroid hormone receptor 1 can be ameliorated by T3 treatment

¹ Psychobiology Department, Universidad Nacional de Educación a Distancia, 28040 Madrid, Spain; ² Instituto de Investigaciones Biomédicas "Alberto Sols," CSIC-UAM, 28029 Madrid, Spain; ³ Department of Cell and Molecular Biology, Karolinska Institute, S-171 77 Stockholm, Sweden

The transcriptional properties of unliganded thyroid hormone receptors are thought to cause the misdevelopment during hypothyroidism of several functions essential for adult life. To specifically determine the role of unliganded thyroid hormone receptor 1 (TR1) in neuronal tissues, we introduced a mutation into the mouse TR1 gene that lowers affinity to thyroid hormone (TH) 10-fold. The resulting heterozygous mice exhibit several distinct neurological abnormalities: extreme anxiety, reduced recognition memory, and locomotor dysfunction. The anxiety and memory deficiencies were relieved by treatment with high levels of TH in adulthood, an effect that correlated with a normalization of GABAergic inhibitory interneurons in the hippocampal CA1 region. In contrast, a post-natal TH treatment was necessary and sufficient for ameliorating the adult locomotor dysfunction. Here, the hormone treatment normalized the otherwise delayed cerebellar development. The data thus identify two novel and distinct functions of an unliganded TR1 during development and adulthood, respectively.

[Keywords: Thyroid hormones; nuclear receptors; cerebellum; hippocampus; GABA]

Received April 6, 2005; revised version accepted July 13, 2005.

Corresponding authors.

⁴ These authors contributed equally to this work.

⁶ E-MAIL jbernal{at}iib.uam.es; FAX 34-1-585-4587.

⁵ E-MAIL bjorn.vennstrom{at}cmb.ki.se; FAX 46-8-348135.

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