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J Physiol Volume 586, Number 7, 1963-1975, April 1, 2008 DOI: 10.1113/jphysiol.2007.149815
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ALIMENTARY

Activity-dependent regulation of tyrosine hydroxylase expression in the enteric nervous system

 J. Chevalier1,2,3, P. Derkinderen1,2,3,4, P. Gomes5, R. Thinard6, P. Naveilhan6, P. Vanden Berghe5 and M. Neunlist1,2,3

1 INSERM, U913, Nantes, F-44093, France
2 Université de Nantes, Faculté de Médecine, Nantes, F-44093, France
3 CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, Nantes, F-44093, France
4 CHU Nantes, Hôtel Dieu, Department of Neurology, Nantes, F-44093, France
5 Center for Gastroenterological Research, KU Leuven, Belgium
6 INSERM, U643, Nantes, F-44093, France

The regulation of neuromediator expression by neuronal activity in the enteric nervous system (ENS) is currently unknown. Using primary cultures of ENS derived from rat embryonic intestine, we have characterized the regulation of tyrosine hydroxylase (TH), a key enzyme involved in the synthesis of dopamine. Depolarization induced either by 40 mM KCl, veratridine or by electrical field stimulation produced a robust and significant increase in the proportion of TH immunoreactive (TH-IR) neurons (total neuronal population was identified with PGP9.5 or Hu) compared to control. This increase in the proportion of TH-IR neurons was significantly reduced by the sodium channel blocker tetrodotoxin (0.5 µM), demonstrating that neuronal activity was critically involved in the effects of these depolarizing stimuli. KCl also increased the proportion of VIP-IR but not nNOS-IR enteric neurons. The KCl-induced increase in TH expression was partly reduced in the presence of the nicotinic receptor antagonist hexamethonium (100 µM), of noradrenaline (1 µM) and of the {alpha}2-adrenoreceptor agonist clonidine (1 µM). Combining pharmacological and calcium imaging studies, we have further shown that L-type calcium channels were involved in the increase of TH expression induced by KCl. Finally, using specific inhibitors, we have shown that both protein kinases A and C as well as the extracellular signal-regulated kinases were required for the increase in the proportion of TH-IR neurons induced by KCl. These results are the first demonstration that TH phenotype of enteric neurons can be regulated by neuronal activity. They could also set the basis for the study of the pathways and mechanisms involved in the neurochemical plasticity observed both during ENS development and in inflammatory enteric neuropathies.

(Received 21 December 2007; accepted after revision 4 February 2008; first published online 7 February 2008)
Corresponding author M. Neunlist: INSERM U913 and Institut des Maladies de l'Appareil Digestif, 1, place Alexis Ricordeau, 44093 Nantes, France.  Email: michel.neunlist{at}univ-nantes.fr

J. Chevalier and P. Derkinderen contributed equally to this work.






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