Thyroid hormone receptor α1 (TRα1) has been implicated in the neurological complications of hypothyroidism, but its exact role in neuronal development and adult brain function has not been clear. Now, Venero and colleagues have shed light on the role of unliganded TRα1 in causing anxiety, memory deficits and motor dysfunction.

In vertebrates, the binding of thyroid hormone to TRα and TRβ triggers many cellular reactions. But when the natural ligand, triiodothyronine (T3), is limiting, for example, in hypothyroidism, TRs form complexes with other proteins such as co-repressors, an interaction that suppresses basal level transcription of target genes that are normally induced by ligand-bound TRs. The apo-forms of TRs are implicated in the abnormal development of the brain during hypothyroidism, which leads to irreversible motor dysfunction and reduced mental capabilities.

The TRα1 receptor accounts for 70–80% of TRs in neuronal tissues and is thought to be the most relevant in the development of the central nervous system. Venero et al. showed that knock-in mice carrying a mutated form of TRα1 (R384C), with a tenfold reduction in affinity for T3, had neurological abnormalities that presented at two stages of brain development.

At 12–14 weeks, TRα1 mutant mice were more anxious and less likely to explore new objects compared with wild-type mice. In the elevated plus maze, knock-in male mice froze more and reared less — both behavioural characteristics of anxiety — than wild-type mice. In addition, TRα1 mutant mice were not as inquisitive about an unfamiliar object as wild-type mice, and showed lower memory recognition for objects that they had already encountered. Although administration of high levels of T3 alleviated the anxious behaviour and restored the exploratory preference of adult mutant mice, symptoms only improved in adults, not juveniles (postnatal days 10–35), which suggests a neurophysiological role for TRα1 in adults.

The authors went on to investigate the effect of TRα1 on locomotor activity. After training on the Rotarod, mice carrying the TRα1 mutation stayed on the rod for shorter periods of time than wild-type mice. Interestingly, although T3 treatment of adult TRα1 mutant mice had no effect on their performance, treatment of juvenile mice (postnatal days 10–35) completely normalized the locomotor activity of adult mutant mice, which suggests that Trα1 has a role in brain development.

In humans, mutations of the TRβ gene result in the syndrome of peripheral resistance to thyroid hormones, but no mutations of TRα1 have been described. The results reported by Venero and co-workers suggest a clinical phenotype of anxiety and locomotor dysfunction without alterations in circulating levels of thyroid hormones. Moreover, these dysfunctions were ameliorated in TRα1 mutant mice by high levels of T3, which suggests that these neurological abnormalities could be circumvented by hormone treatment at the appropriate time.