Thyroid hormones (TH) are important for development and function of the mammalian brain. Most TH actions are mediated by binding to nuclear receptors (TR)and regulation of gene expression. There are 4 TR isoforms, encoded by the THRA and THRBgenes. Although all of them are expressed in brain the TRa1 isoform accounts for more than 70% of all TR protein. In the cerebellum TH promotes granular cell (GC) migration and Purkinje cell (PC) differentiation mostly through TRa1, but TRa1 knock out mice do not display alterations in GC migration or PC differentiation. Furthermore, induction of hypothyroidism in TRa1 knock out mice does not affect these cell populations. The effects of hypothyroidism are therefore a consequence of unliganded receptor activity. In agreement with this, expression of a mutant TRa1, with dominant negative properties affected cerebellar development and motor performance. Therefore the hypothyroid phenotype may not reflect true developmental actions of the hormone, but interference of unliganded receptors with processes which do not require thyroid hormones. TRa1 is involved in functions previously unrecognized, such as control of differentiation of specific GABAergic interneurons of the cerebellum and hippocampus. The latter has important consequences in the regulation of behaviour. For example, TRa1 deletion, or expression of its dominant negative mutant version induced behavioural changes in adult mice indicating extreme anxiety. These results also demonstrate that TRa1 has important roles not only during development, but also in the adult brain, such as maintenance of hippocampal GABAergic interneurons and modulation of behaviour.