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Thyroid hormones act as a timer for the postnatal maturation of parvalbumin neurons in mouse neocortex [RUN54]

ABSTRACT: A finely tuned balance between excitation and inhibition is essential for proper brain function. Disruptions in the GABAergic system, which alter this equilibrium, are a common feature in various types of neurological disorders. Understanding GABAergic neuron maturation processes is thus currently a major challenge in basic neuroscience. Thyroid hormones (THs) are required for proper maturation of parvalbumin-expressing GABAergic interneurons in the mouse neocortex. However, the timeline of this TH action has yet to be elucidated. Here, we used several mouse models expressing dominant negative mutations of the TH nuclear receptor α1 (TRα1), to better define the time window during which THs promote the postnatal maturation of parvalbumin neurons. Histological observations revealed that the action of TH during the first three postnatal weeks was necessary to initiate the expression of parvalbumin and the elaboration of a specialized extracellular matrix called the perineuronal net. By contrast, after the third postnatal week, TH action on parvalbumin neuron maturation appeared to be somewhat dispensable. Transcriptome analysis of neocortical GABAergic neurons two weeks after birth identified a small set of putative target genes for TRα1. These genes are at the origin of the postnatal remodeling of the repertoire of ions channels and the elaboration of perineuronal nets. These data suggest that THs act as a timer to define the temporal boundaries of the critical period of heightened cortical plasticity, which plays a fundamental role in the development of neuronal circuits.

ORGANISM(S): Mus musculus

PROVIDER: GSE290207 | GEO | 2026/04/22

REPOSITORIES: GEO

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Project description:Thyroid hormones (THs) play a critical role in development and throughout adulthood. THs act through the thyroid receptor (TR), which binds to the TH response element (TRE) to regulate the expression of target genes. Although TH action has been studied for decades, surprisingly few TREs have been well validated and characterized. In this study we used chromatin immunoprecipitation followed by microarray analysis (ChIP-chip) to identify TR-binding sites in juvenile (postnatal day 15) mice liver. Microarray analysis revealed twelve TR-binding sites consistent between all analyzed samples. In silico analysis was carried out to search for moderately conserved classic TRE sequences within these novel binding regions, which led to the identification of six candidate TREs within three binding regions. Luciferase reporter assays confirmed the presence of a TRE in the promoter region of DEAD (Asp-Glu-Ala-Asp) box polypeptide 54 (Ddx54) and thyroid hormone responsive SPOT14 (Thrsp). The TR/retinoid X receptor (RXR) heterodimer and RXR homodiner were shown to bind the promoter region of Ddx54 and drive gene expression in the presence of 9-cis-retinoic acid (9cRA). The promoter region of Thrsp was shown to allow binding of the TR/RXR heterodimer, and both T3 and 9cRA were able to significantly increase luciferase activity. The RXR homodimer was also able to bind the response element in the promoter region of Thrsp and increase luciferase activity. Overall, ChIP-chip analysis revealed a relatively limited number of TR-binding sites in juvenile mouse liver despite previous studies showing that numerous genes can be affected by TH disruption at that developmental stage, suggesting that TH action may also be mediated through other intermediates. Collectively the results provide an important step towards characterizing TR-binding sites and identifying the underlying drivers of TR-gene regulation. Three samples were analyzed (total input and immunoprecipitated for each samples).

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Thyroid hormones act as a timer for the postnatal maturation of parvalbumin neurons in mouse neocortex [RUN54]

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