Guadaño-Ferraz A, Benavides-Piccione R, Venero C, Lancha C, Vennström B, Sandi C, DeFelipe J, Bernal J
Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain.
Mol Psychiatry. 2003 Jan;8(1):30-8. doi: 10.1038/sj.mp.4001196.
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, TRalpha and TRbeta, encode several receptor isoforms with specific functions defined in many tissues but not in the brain. Mutations in the TRbeta gene cause the syndrome of peripheral resistance to thyroid hormone; however, no alterations of the TRalpha gene have been described in humans. Here we demonstrate that mice lacking the TRalpha1 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 TRalpha1 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.
大脑的发育和功能依赖于甲状腺激素（T3），T3通过核激素受体发挥作用。T3受体（TRs）是转录因子，可通过激素依赖性或非依赖性方式激活或抑制靶基因表达。两个不同的基因，TRα和TRβ，编码几种受体亚型，其特定功能在许多组织中已明确，但在大脑中尚未明确。TRβ基因突变会导致外周甲状腺激素抵抗综合征；然而，人类中尚未发现TRα基因的改变。在此我们证明，缺乏TRα1亚型的小鼠表现出海马起源的行为异常，旷场试验和恐惧条件反射试验均表明了这一点。在旷场试验中，突变小鼠的探索行为比野生型小鼠少。在情境恐惧条件反射试验中，训练1周后进行测试时，突变小鼠的僵立反应比野生型对照显著更高。这些发现与突变小鼠CA1锥体神经元上较少的γ-氨基丁酸能终末相关。我们的结果表明，TRα1参与海马结构和功能的调节，并增加了这种受体亚型的缺失或突变可能导致人类行为改变甚至精神综合征的可能性。
