Gastroenterology
Volume 138, Issue 4 , Pages 1491-1501, April 2010

Glial Cell–Derived Neurotrophic Factor Enhances Synaptic Communication and 5-Hydroxytryptamine 3a Receptor Expression in Enteric Neurons

  • Fanning Zeng

      Affiliations

    • Corresponding Author InformationReprint requests Address requests for reprints to: Fanning Zeng, MD, PhD, Gastrointestinal Disease Area, Novartis Horsham Research Centre, Wimblehurst Road, Horsham, RH12 5AB, United Kingdom. fax: (44) 1403-323054
    • ,
  • Robert P. Watson
    • ,
  • Mark S. Nash

Gastrointestinal Disease Area, Novartis Horsham Research Centre, Horsham, United Kingdom

Received 4 August 2009; accepted 18 November 2009. published online 30 November 2009.

Background & Aims

Glial cell–derived neurotrophic factor (GDNF) is essential for the development of the enteric nervous system during embryogenesis. We have observed the presence of Gdnf transcripts in the gastrointestinal tract of adult mice, and its early up-regulation after inflammation. We therefore investigated the effects of GDNF on enteric neuronal function in vitro.

Methods

Primary neuronal cultures were established from isolated myenteric plexi, and characterized by immunostaining and Ca2+ imaging. Gene expression of several ion channels was analyzed by quantitative polymerase chain reaction (PCR) and the electrophysiologic properties of the neurons were studied by patch clamp.

Results

GDNF enhanced synaptogenesis and intercellular communication in primary myenteric neuronal cultures. Expression profiling revealed that GDNF exposure results in an up-regulation of Htr3a expression in the cultures and a similar increase was observed in inflamed colonic tissue where Gdnf expression was also increased. The increased Htr3a expression was accompanied by a functional increase in the response of neurons to acute challenge with 5-hydroxytryptamine (5-HT). GDNF treatment also caused inhibition of delayed rectifying voltage-gated potassium (Kv) currents, which correlated with the up-regulation of Htr3a and 5-HT–induced responses. Furthermore, pharmacologic blockade of Kv channels mimicked the effect of GDNF by increasing Htr3a expression as well as enhancing 5-HT–induced responses in the cultured myenteric neurons.

Conclusions

GDNF promotes synaptic communication in cultured myenteric neurons. It also up-regulates 5-HT3a-receptor expression via modulation of Kv channel activity. Up-regulation of Gdnf after gastrointestinal inflammation might play an important role in the pathophysiology of gastrointestinal diseases.

Keywords: GDNF, Enteric Neuron, 5-HT3a Receptor, Kv Channel

Abbreviations used in this paper: AP, action potential, ENS, enteric nervous system, GDNF, Glial cell–derived neurotrophic factor, GI, gastrointestinal, 5-HT, 5-hydroxytryptamine (serotonin), Kv channel, voltage-gated potassium channel, PCR, polymerase chain reaction, PMA, phorbol 12- myristate-13-acetate, TEA, tetraethylammonium

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 Conflicts of interest The authors disclose no conflicts.

 Funding This study was supported by a postdoctoral fellowship from Novartis Institute for Biomedical Research (F.Z.).

PII: S0016-5085(09)02100-3

doi:10.1053/j.gastro.2009.11.048

Gastroenterology
Volume 138, Issue 4 , Pages 1491-1501, April 2010

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