Brain development and function are dependent on thyroid hormone (T3), which acts through nuclear hormone receptors. T3 receptors (TRs) are transcription factors that activate or suppress target gene expression in a hormone-dependent or-independent fashion. Two distinct genes, TRα and TRβ, encode several receptor isoforms with specific functions defined in many tissues but not in the brain. Mutations in the TRβ gene cause the syndrome of peripheral resistance to thyroid hormone; however, no alterations of the TRα gene have been described in humans. Here we demonstrate that mice lacking the TRα1 isoform display behavioral abnormalities of hippocampal origin, as shown by the open field and fear conditioning tests. In the open field test mutant mice revealed less exploratory behavior than wild-type mice. In the contextual fear conditioning test mutant mice showed a significantly higher freezing response than wild-type controls when tested 1 week after training. These findings correlated with fewer GABAergic terminals on the CA1 pyramidal neurons in the mutant mice. Our results indicate that TRα1 is involved in the regulation of hippocampal structure and function, and raise the possibility that deletions or mutations of this receptor isoform may lead to behavioral changes or even psychiatric syndromes in humans.