A Pivotal Genetic Program Controlled by Thyroid Hormone during the Maturation of GABAergic Neurons

• Published in: iScience 2020-03, Vol.23 (3), p.100899, Article 100899
• Main Authors: Richard, Sabine, Guyot, Romain, Rey-Millet, Martin, Prieux, Margaux, Markossian, Suzy, Aubert, Denise, Flamant, Frédéric
• Format: Article
• Language: English
• Subjects: Developmental Neuroscience; Engineering Sciences; Molecular Neuroscience; Neuroscience
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2020.100899

Mammalian brain development critically depends on proper thyroid hormone signaling, via the TRα1 nuclear receptor. The downstream mechanisms by which TRα1 impacts brain development are currently unknown. In order to investigate these mechanisms, we used mouse genetics to induce the expression of a dominant-negative mutation of TRα1 specifically in GABAergic neurons, the main inhibitory neurons in the brain. This triggered post-natal epileptic seizures and a profound impairment of GABAergic neuron maturation in several brain regions. Analysis of the transcriptome and TRα1 cistrome in the striatum allowed us to identify a small set of genes, the transcription of which is upregulated by TRα1 in GABAergic neurons and which probably plays an important role during post-natal maturation of the brain. Thus, our results point to GABAergic neurons as direct targets of thyroid hormone during brain development and suggest that many defects seen in hypothyroid brains may be secondary to GABAergic neuron malfunction. [Display omitted] •GABAergic neurons are a direct target of thyroid hormone in the developing brain•Impaired TH/TRα1 signaling severely impairs the development of GABAergic neurons•GABAergic-specific genes directly targeted by TH/TRα1 signaling have been listed•A defect in the GABAergic system is expected in patients with a THRA mutation Neuroscience; Molecular Neuroscience; Developmental Neuroscience