Elsevier

Neuroscience

Volume 168, Issue 2, 30 June 2010, Pages 573-589
Neuroscience

Regeneration, Repair, and Developmental Neuroscience
Research Paper
Regulation of early spontaneous network activity and GABAergic neurons development by thyroid hormone

https://doi.org/10.1016/j.neuroscience.2010.03.039Get rights and content

Abstract

Early in development spontaneous activity modulates survival and connectivity of neurons and thus plays a crucial role in the formation of neural networks. The emergence of synchronous activity in cultured neocortical networks initially is driven by large GABAergic interneurons. Here we studied the impact of thyroid hormone on early network development and especially on the development of large GABAergic neurons. Triiodothyronine enhances the frequency of early spontaneous synchronous network activity and an overall increase in network connectivity is indicated by the increased density of glutamatergic and GABAergic synapses. The hormone-induced increase of activity parallels cell type–specific changes in neuronal soma size and cell density, with strong effects on somatic and axonal growth of large GABAergic interneurons. Interestingly, large GABAergic neuron growth is both activity- and hormone-regulated. Blocking neuronal activity by tetrodotoxin or the glutamate receptor blockers D-2-amino-5-phosphonopentanoic acid and 6-cyano-7-nitroquinoxaline-2,3-dione disodium reveals a direct contribution of triiodothyronine to somatic growth, which also precedes the formation of synchronous network activity. The hormone-mediated effects on spontaneous activity and on large GABAergic neurons growth can be blocked by the nuclear thyroid hormone receptors antagonist 1-850. Thus, our data suggest that triiodothyronine actions result in functional maturation of early cortical networks and cell type–specific structural alterations. The increase in spontaneous activity might initially follow the growth of the large GABAergic neurons, which show an exquisite sensitivity to the presence of thyroid hormones. For the most part, however, the hormone-mediated growth of the GABAergic neurons relies strongly on the maturation of glutamatergic synaptic activity.

Section snippets

Cell culture

Neuronal cultures were prepared from E16 rat cortex and cultured for 7 to 21 days in serum-free N2 medium. Cortical neurons were cultivated in the presence of a surrounding glial feeding layer. All experimental procedures were approved by local government authorities.

Each acid-cleaned cover slip was fitted to a 20-mm hole in the bottom of a 60-mm Petri dish, and was treated overnight with poly-D-lysine (0.1 mg/ml in borate buffer, pH 8.5, 36 °C). Astroglial cultures were prepared from cerebral

Development of spontaneous network activity

As in the neonatal cerebral cortex, synchronized rhythmic activity develops spontaneously in cortical networks formed by embryonic neurons in culture (Muramoto et al., 1993, de Lima et al., 1997, Voigt et al., 2005). The slow rhythmic synchronous Ca2+ transients seen with imaging techniques reflect bursts of action potentials recorded in single cells with the patch clamp technique (Opitz et al., 2002, Voigt et al., 2005). To illustrate the development of synchronous network activity in cultured

Hormonal modulation of network activity and synaptic maturation

Converging evidence suggests that during early neocortical development synchronous network activity emerges when neurons become interconnected. Synchronous events with very low frequency develop to reach maximal cellular participation, which includes nearly all neurons (Garaschuk et al., 2000, Opitz et al., 2002, Corlew et al., 2004). As development proceeds, synchronous events with lower cellular participation and higher burst frequency become interposed to events with higher participation,

Acknowledgments

The authors thank B. Adam and A. Ritter for expert technical assistance. This work was supported by Land Sachsen Anhalt (LSA 3431A/0302M) and Bundesministerium für Bildung und Forschung (BMBF/BNCN 016Q0702).

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