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Changes in enteric neurone phenotype and intestinal functions in a transgenic mouse model of enteric glia disruption
  1. A-C Aubé1,*,
  2. J Cabarrocas2,*,
  3. J Bauer3,
  4. D Philippe4,
  5. P Aubert1,
  6. F Doulay5,
  7. R Liblau2,
  8. J P Galmiche1,
  9. M Neunlist1
  1. 1INSERM, U539, Nantes, France, Institut des Maladies de l’Appareil Digestif, Nantes, France, and Université Nantes, Nantes, France
  2. 2INSERM, U563, Toulouse, France
  3. 3Centre for Brain Research, Vienna, Austria
  4. 4INSERM EPI 0114, Swynghedauw Hospital, Lille, France
  5. 5INRA, Nantes, France
  1. Correspondence to:
    Dr M Neunlist
    INSERM U 539, 1, Place Alexis Ricordeau, 44035 Nantes, France; michel.neunlist{at}univ-nantes.fr

Abstract

Aims: The influence of enteric glia on the regulation of intestinal functions is unknown. Our aim was to determine the phenotype of enteric neurones in a model of glia alterations and the putative changes in intestinal motility and permeability.

Methods: Transgenic mice expressing haemagglutinin (HA) in glia were used. Glia disruption was induced by injection of activated HA specific CD8+ T cells. Control mice consisted of non-transgenic littermates injected with activated HA specific CD8+ T cells. Immunohistochemical staining for choline acetyltransferase (ChAT), substance P (SP), vasoactive intestinal peptide (VIP), and nitric oxide synthase (NOS) was performed on jejunal submucosal plexus (SMP) and myenteric plexus (MP). Neurally induced jejunal muscle activity was characterised in vitro. Gastrointestinal transit and paracellular permeability were measured using fluorescein isothiocyanate-dextran markers.

Results: CD3 positive T cells infiltrates were observed in the MP of transgenic mice. In the SMP, the proportions of VIP and SP positive neurones decreased in transgenic mice compared with control mice. ChAT remained unchanged. In the MP, the proportions of ChAT and NOS positive neurones increased and decreased, respectively, in transgenic mice. In contrast, VIP and SP remained unchanged. Neurally mediated jejunal relaxation was lower in transgenic mice than in controls. This relaxation was reduced by NG-nitro-L-arginine methyl ester in control mice but not in transgenic mice. Gastrointestinal transit was delayed and intestinal permeability increased in transgenic mice compared with control mice.

Conclusion: Glia disruption induces changes in the neurochemical coding of enteric neurones, which may partly be responsible for dysfunctions in intestinal motility and permeability.

  • BDNF, brain derived neurotrophic factor
  • ChAT, choline acetyltransferase
  • CNS, central nervous system
  • CS, cross sectional area
  • DMEM, Dulbecco’s modified Eagle’s medium
  • EFS, electrical field stimulation
  • EGCs, enteric glial cells
  • ENS, enteric nervous system
  • FITC, fluorescein isothiocyanate
  • GDNF, glial derived neurotrophic factor
  • GFAP, glial fibrillary acidic protein
  • HA, haemagglutinin
  • IGC, intestinal geometric centre
  • IFN-γ, interferon γ
  • IL, interleukin
  • L-NAME, NG-nitro-L-arginine methyl ester
  • MP, submucosal plexus
  • NGF, nerve growth factor
  • NO, nitric oxide
  • NOS, nitric oxide synthase
  • NSE, neurone specific enolase
  • NT-3, neurotrophin 3
  • PBS, phosphate buffered saline
  • PCR, polymerase chain reaction
  • SMP, submucosal plexus
  • SNP, sodium nitroprusside
  • SP, substance P
  • TCR, T cell receptor
  • TNF-α, tumour necrosis factor α
  • TTX, tetrodotoxin
  • VIP, vasoactive intestinal peptide
  • enteric glia
  • permeability
  • motility
  • enteric nervous system
  • nitric oxide synthase
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Footnotes

  • * A-C Aubé and J Cabarrocas contributed equally to this study.

  • Published online first 19 October 2005

  • Conflict of interest: None declared.

  • Parts of this study were presented at the Annual Meetings of the American Gastroenterological Association, Orlando, Florida, 18–22 May 2003, and New Orleans, 15–20 May 2004.

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