TY - JOUR

T1 - Locomotor deficiencies and aberrant development of subtype-specific GABAergic interneurons caused by an unliganded thyroid hormone receptor α1

AU - Wallis, Karin

AU - Sjögren, Maria

AU - Van Hogerlinden, Max

AU - Silberberg, Gilad

AU - Fisahn, André

AU - Nordström, Kristina

AU - Larsson, Lars

AU - Westerblad, Håkan

AU - De Escobar, Gabriela Morreale

AU - Shupliakov, Oleg

AU - Vennström, Björn

PY - 2008/2/20

Y1 - 2008/2/20

N2 - Thyroid hormone (TH) deficiency during development causes severe and permanent neuronal damage, but the primary insult at the tissue level has remained unsolved. We have defined locomotor deficiencies in mice caused by a mutant thyroid hormone receptor α1 (TRα1) with potent aporeceptor activity attributable to reduced affinity to TH. This allowed identification of distinct functions that required either maternal supply of TH during early embryonic development or sufficient innate levels of hormone during late fetal development. In both instances, continued exposure to high levels of TH after birth and throughout life was needed. The hormonal dependencies correlated with severely delayed appearance of parvalbumin-immunoreactive GABAergic interneurons and increased numbers of calretinin-immunoreactive cells in the neocortex. This resulted in reduced numbers of fast spiking interneurons and defects in cortical network activity. The identification of locomotor deficiencies caused by insufficient supply of TH during fetal/perinatal development and their correlation with subtype-specific interneurons suggest a previously unknown basis for the neuronal consequences of endemic cretinism and untreated congenital hypothyroidism, and specifies TRα1 as the receptor isoform mediating these effects.

AB - Thyroid hormone (TH) deficiency during development causes severe and permanent neuronal damage, but the primary insult at the tissue level has remained unsolved. We have defined locomotor deficiencies in mice caused by a mutant thyroid hormone receptor α1 (TRα1) with potent aporeceptor activity attributable to reduced affinity to TH. This allowed identification of distinct functions that required either maternal supply of TH during early embryonic development or sufficient innate levels of hormone during late fetal development. In both instances, continued exposure to high levels of TH after birth and throughout life was needed. The hormonal dependencies correlated with severely delayed appearance of parvalbumin-immunoreactive GABAergic interneurons and increased numbers of calretinin-immunoreactive cells in the neocortex. This resulted in reduced numbers of fast spiking interneurons and defects in cortical network activity. The identification of locomotor deficiencies caused by insufficient supply of TH during fetal/perinatal development and their correlation with subtype-specific interneurons suggest a previously unknown basis for the neuronal consequences of endemic cretinism and untreated congenital hypothyroidism, and specifies TRα1 as the receptor isoform mediating these effects.

KW - Calretinin

KW - GABA

KW - Hypothyroid

KW - Interneuron

KW - Locomotion

KW - Parvalbumin

KW - Thyroid hormone receptor

UR - http://www.scopus.com/inward/record.url?scp=39749171735&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.5163-07.2008

DO - 10.1523/JNEUROSCI.5163-07.2008

M3 - Article

C2 - 18287507

AN - SCOPUS:39749171735

VL - 28

SP - 1904

EP - 1915

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 8

ER -