Abstract
Early in neocortical network development, triiodothyronine (T3) promotes GABAergic neurons' population increase, their somatic growth and the formation of GABAergic synapses. In the presence of T3, GABAergic interneurons form longer axons and conspicuous axonal arborizations, with an increased number of putative synaptic boutons. Here we show that the increased GABAergic axonal growth is positively correlated with the proximity to non-GABAergic neurons (non-GABA). A differential innervation emerges from a T3-dependent decrease of axonal length in fields with low density of neuronal cell bodies, combined with an increased bouton formation in fields with high density of neuronal somata. T3 addition to deprived networks after the first 2 weeks of development did not rescue deficits in the GABAergic synaptic bouton distribution, or in the frequency and duration of spontaneous bursts. During the critical 2-week-period, GABAergic signaling is depolarizing as revealed by calcium imaging experiments. Interestingly, T3 enhanced the expression of the potassium-chloride cotransporter 2 (KCC2), and accelerated the developmental shift from depolarizing to hyperpolarizing GABAergic signaling in non-GABA. The T3-related increase of spontaneous network activity was remarkably reduced after blockade of either tropomyosin-receptor kinase B (trkB) or mammalian target of rapamycin (mTOR) pathways. T3-dependent increase in GABAergic neurons' soma size was mediated mainly by mTOR signaling. Conversely, the T3-dependent selective increase of GABAergic boutons near non-GABAergic cell bodies is mediated by trkB signaling only. Both trkB and mTOR signaling mediate T3-dependent reduction of the GABAergic axon extension. The circuitry context is relevant for the interaction between T3 and trkB signaling, but not for the interactions between T3 and mTOR signaling.
Highlights
Thyroid hormone has a diverse range of actions in the development and function of the CNS and plays a prominent role in neocortical development (Gilbert et al, 2012)
The developmental change of GABA action is mediated by a decreased expression of the sodium-potassium-chloride cotransporter Na+-K+-Cl− cotransporter (NKCC1), which accumulates chloride in young neurons, and by an increased expression of the potassium chloride cotransporter K+-Cl− cotransporter 2 (KCC2), which extrudes chloride from mature neurons (Ben-Ari et al, 2007; Blaesse et al, 2009)
A Western blot analysis showed that NKCC1 expression in T3+ cultures increased from 7 to 14 Days in vitro (DIV), and dropped from 14 to 21 DIV (Figures 1A,C)
Summary
Thyroid hormone has a diverse range of actions in the development and function of the CNS and plays a prominent role in neocortical development (Gilbert et al, 2012). Thyroid hormone modulates the development and function of GABAergic interneurons in vivo and in vitro (Gilbert et al, 2007; Westerholz et al, 2010). T3-mediated development of GABAergic neurons in vitro is paralleled by an accelerated maturation of early network activity (Westerholz et al, 2010). This modulation of neuronal activity by T3 during the formation of the network explains, at least partially, the effects of the hormone on the development of GABAergic neurons (Westerholz et al, 2010)
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