Local Thyroid Hormone Action in Brain Development

Abstract

Proper brain development essentially depends on the timed availability of sufficient amounts of thyroid hormone (TH). This, in turn, necessitates a tightly regulated expression of TH signaling components such as TH transporters, deiodinases, and TH receptors in a brain region- and cell-specific manner from early developmental stages onwards. Abnormal TH levels during critical stages, as well as mutations in TH signaling components that alter the global and/or local thyroidal state, result in detrimental consequences for brain development and neurological functions that involve alterations in central neurotransmitter systems. Thus, the question as to how TH signaling is implicated in the development and maturation of different neurotransmitter and neuromodulator systems has gained increasing attention. In this review, we first summarize the current knowledge on the regulation of TH signaling components during brain development. We then present recent advances in our understanding on how altered TH signaling compromises the development of cortical glutamatergic neurons, inhibitory GABAergic interneurons, cholinergic and dopaminergic neurons. Thereby, we highlight novel mechanistic insights and point out open questions in this evolving research field.

Keywords: GABA; T3; T4; acetylcholine; dopamine; glutamate; thyroid hormone.

Figure 1

Schematic representation of different stages of cortical glutamatergic pyramidal cell development. Apical radial glia cells give rise to intermediate progenitors, which transform into neuronal progenitors that migrate along the radial glia scaffold to reach their destined position. In the developing cortical plate, progenitors mature into pyramidal cells, the dominant neuronal cell type in the cerebral cortex, which release the neurotransmitter glutamate. Expression of TH transporters, deiodinases, and TRs is depicted as known for the human and mouse cerebral cortex. TH-regulated factors such as Shh, Reelin, and Ephrins have been implicated in the regulation of corticogenesis. Gray-colored cells indicate radial glia cells (apical and basal) that provide the fiber scaffold for progenitor migration. VZ—ventricular zone. Created with BioRender.com.

Figure 2

TH’s effects on the development of inhibitory GABAergic interneurons. Interneuron progenitors are generated in the ganglionic eminences, with the medial ganglionic eminence (MGE) giving rise to the PV+ and SST+ subtypes, whereas CR+ interneurons are born in the caudal ganglionic eminence (CGE). Progenitor development is regulated by T3 target genes such as Shh, which is critical for the maintenance of Nkx2.1 expression. Likewise, T3-regulated Wnt components may influence early interneuron progenitor development. Progenitors migrate out of the ganglionic eminence to populate brain areas such as the forming cerebral cortex. Lhx6 is implicated in cellular migration and is itself TH sensitive and downstream of the T3/Shh/Nkx2.1 pathway. Interneuron maturation is further governed by TH-regulated Bdnf and Bmp4. Mature interneurons can be distinguished according to different classification criteria, such as the expression of marker proteins PV, SST, or CR. Expression of TH transporters, deiodinases, and TRs is depicted as known from murine and human studies. LGE—lateral ganglionic eminence; VZ—ventricular zone. Created with BioRender.com.