GDNF Increases Inhibitory Synaptic Drive on Principal Neurons in the Hippocampus via Activation of the Ret Pathway

Apostolos Mikroulis, Eliška Waloschková, Johan Bengzon, David Woldbye, Lars H Pinborg, Bo Jespersen, Anna Sanchez Avila, Zsofia I Laszlo, Christopher Henstridge, Marco Ledri, Merab Kokaia


Glial cell line-derived neurotrophic factor (GDNF) has been shown to counteract seizures when overexpressed or delivered into the brain in various animal models of epileptogenesis or chronic epilepsy. The mechanisms underlying this effect have not been investigated. We here demonstrate for the first time that GDNF enhances GABAergic inhibitory drive onto mouse pyramidal neurons by modulating postsynaptic GABAA receptors, particularly in perisomatic inhibitory synapses, by GFRα1 mediated activation of the Ret receptor pathway. Other GDNF receptors, such as NCAM or Syndecan3, are not contributing to this effect. We observed similar alterations by GDNF in human hippocampal slices resected from epilepsy patients. These data indicate that GDNF may exert its seizure-suppressant action by enhancing GABAergic inhibitory transmission in the hippocampal network, thus counteracting the increased excitability of the epileptic brain. This new knowledge can contribute to the development of novel, more precise treatment strategies based on a GDNF gene therapy approach.

Original languageEnglish
Article number13190
JournalInternational Journal of Molecular Sciences
Issue number21
Publication statusPublished - 29 Oct 2022


  • Humans
  • Mice
  • Animals
  • Glial Cell Line-Derived Neurotrophic Factor/metabolism
  • Glial Cell Line-Derived Neurotrophic Factor Receptors/genetics
  • Neurons/metabolism
  • Hippocampus/metabolism
  • Synapses/metabolism
  • Proto-Oncogene Proteins c-ret/genetics


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