Thyroid hormone receptor alpha plays an essential role in the normalisation of adult-onset hypothyroidism-related hypoexpression of synaptic plasticity target genes in striatum

Thyroid hormones (TH), particularly thyroxine (T4) and triiodothyro-nine (3,5,3¢-triiodothyronine, T3), are known to have pleiotrophiceffects in various tissues, including brain, liver, heart, kidney, lung,bone and adipose tissue. The brain is an important target for TH.TH deficiency during the foetal and postnatal periods in humansmay cause irreversible mental retardation, as seen in cretinism, aswell as neurological and behavioural deficits, and long-lasting irre-versible motor dysfunctions (1, 2). In addition to this well-known,essential role of TH during the normal development of the centralnervous system, some studies suggest that thyroid function abnor-malities in adulthood may also have profound behavioural conse-quences, such as anxiety, depressive symptoms and impairedmemory (3, 4).The main active compound at the genomic level is T3, which isessentially formed in extrathyroidal tissues from T4 after deiodin-ation (5). T3 action is mediated by specific nuclear receptors (TR),functioning as ligand-dependent transcription factors to increase ordecrease the expression of target genes. There are two TR genes:TRa and TRb, which encode nine proteins, generated by alternativesplicing and differential promoter usage. Among these, only fourreceptor isoforms (TRa1, TRb1, TRb2 and TRb3) have intact DNAand hormone-binding domains (1). The role of the nonreceptor iso-forms (TRa2, TRa3, DTRa1, DTRa2 and DTRb3) is still unclear (6). Inadult rodent brains, TRa1 accounts for a large fraction of all TRreceptors in the brain, whereas TRb transcripts (b1 and b2) aredetected in few areas (7–9). Among T3 target genes in the brain,some code for TRs and others for neurogranin (RC3 or Nrgn) andRas homologue enriched in striatum (Rhes or Rasd2). These proteinsare co-expressed in the main striatal neurones, medium-sizedspiny cells, where they show a strong dependence on TH (10–12).