Anxiety, memory impairment, and locomotor dysfunction caused by a mutant thyroid hormone receptor alpha1 can be ameliorated by T3 treatment.
The transcriptional properties of unliganded thyroid hormone receptors are thought to cause the misdevelopment during hypothyroidism of several functions essential for adult life. To specifically determine the role of unliganded thyroid hormone receptor alpha1 (TRalpha1) in neuronal tissues, we introduced a mutation into the mouse TRalpha1 gene that lowers affinity to thyroid hormone (TH) 10-fold. The resulting heterozygous mice exhibit several distinct neurological abnormalities: extreme anxiety, reduced recognition memory, and locomotor dysfunction. The anxiety and memory deficiencies were relieved by treatment with high levels of TH in adulthood, an effect that correlated with a normalization of GABAergic inhibitory interneurons in the hippocampal CA1 region. In contrast, a post-natal TH treatment was necessary and sufficient for ameliorating the adult locomotor dysfunction. Here, the hormone treatment normalized the otherwise delayed cerebellar development. The data thus identify two novel and distinct functions of an unliganded TRalpha1 during development and adulthood, respectively.
Venero
César
C
Psychobiology Department, Universidad Nacional de Educación a Distancia, 28040 Madrid, Spain.
Guadaño-Ferraz
Ana
A
Herrero
Ana Isabel
AI
Nordström
Kristina
K
Manzano
Jimena
J
de Escobar
Gabriella Moreale
GM
Bernal
Juan
J
Vennström
Björn
B
D000818:Animals; D001007:Anxiety / Q000188:drug therapy*; D020233:Gait Disorders, Neurologic / Q000188:drug therapy*; D006579:Heterozygote; D006624:Hippocampus / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D007037:Hypothyroidism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007395:Interneurons / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010320:Parvalbumins / Q000378:metabolism; D011863:Radioimmunoassay; D037021:Thyroid Hormone Receptors alpha / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D014284:Triiodothyronine / Q000494:pharmacology*
D010320:Parvalbumins; D037021:Thyroid Hormone Receptors alpha; D014284:Triiodothyronine