Biology subjects

Markossian, S.

Publications and source records attributed to Markossian, S..

3 recordsLinked to original sources

bioRxiv2024

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

Thyroid hormones (THs) are required for proper maturation of parvalbumin-expressing GABAergic interneurons in the mouse neocortex, which function is essential to maintain a proper balance between neuronal excitation and inhibition. 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 1 (TR1), to better define the time window during which THs promote the maturation of parvalbumin neurons. The action of THs during the first three postnatal weeks appears to be necessary to initiate the elaboration of a specialized extracellular matrix called the perineuronal net. Transcriptome analysis identified a small set of putative target genes for TR1, which 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. Significance statementThyroid hormones exert a major influence on late neurodevelopment, acting directly on gene expression by binding to nuclear receptors present in all cell types. This study reports the discovery of a direct link between the transcriptional regulation exerted by the thyroid hormones in GABAergic neurons and the timing of the critical period of heightened plasticity. This provides a general framework to understand the pathology associated with altered thyroid hormone signaling.

developmental biology↗

bioRxiv2024

Thyroid hormones maintain parvalbumin neuron functions in mouse neocortex

Parvalbumin-expressing GABAergic interneurons play a key role in maintaining the excitation-inhibition balance in the mammalian neocortex. While postnatal maturation of parvalbumin neurons is highly sensitive to thyroid hormone deficiency, the role of these hormones in mature parvalbumin neurons remains poorly understood. Here, we addressed the possibility that thyroid hormones are also required to maintain the function of mature parvalbumin neurons in the mouse neocortex. To this end, Cre/loxP recombination system was used to express a dominant-negative mutated receptor of thyroid hormones to selectively eliminate thyroid hormone signaling in parvalbumin neurons after the onset of parvalbumin expression. We analyzed the neocortical phenotype of these mice by combining genomics, histology, electrophysiology, sleep recordings and behavioral analysis. In the mutant mice, gene expression analysis revealed a decreased expression of key perineuronal net components. parvalbumin neuron excitability was decreased and mice displayed behavioral hyperactivity and increased susceptibility to epileptic seizures. Additionally, sleep analysis revealed that mutant mice spent more time awake, and had a delayed transition to sleep. Electrophysiological recordings further demonstrated altered gamma oscillations in the somatosensory cortex. The findings of this study underscore that thyroid hormones are essential not only for the differentiation of parvalbumin interneurons, but also for the maintenance of their inhibitory function after the onset of parvalbumin expression. As a consequence, alterations in thyroid hormone signaling, during development or in adulthood, may contribute to the occurrence of neurological and psychiatric disorders involving altered cortical oscillations.

neuroscience↗

bioRxiv2019

A pivotal genetic program controlled by thyroid hormone during the maturation of GABAergic neurons in mice

In mammals, brain development is critically dependent on proper thyroid hormone signaling, via the TR1 nuclear receptor. However, the downstream mechanisms by which TR1 impacts brain development are currently unknown, notably because this receptor is expressed ubiquitously from early stages of development. In order to better define the function of TR1 in the developing brain, we used mouse genetics to induce the expression of a dominant-negative mutation of the receptor specifically in GABAergic neurons, the main inhibitory neurons in the brain, which were previously identified as sensitive to hypothyroidism. This triggered post-natal epileptic seizures, reflecting a profound impairment of GABAergic neuron maturation in different brain areas. Analysis of transcriptome and TR1 cistrome also allowed us to identify a small set of genes, the transcription of which is upregulated by TR1 in GABAergic neurons during post-natal maturation of the striatum and which probably play an important role during neurodevelopment. 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.

developmental biology↗