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

Mikroulis, Apostolos LU ; Waloschková, Eliška LU ; Bengzon, Johan LU ; Woldbye, David ; Pinborg, Lars H ; Jespersen, Bo ; Avila, Anna Sanchez ; Laszlo, Zsofia I ; Henstridge, Christopher and Ledri, Marco LU , et al. (2022) In International Journal of Molecular Sciences 23(21). p.1-22
Abstract

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... (More)

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.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
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
in
International Journal of Molecular Sciences
volume
23
issue
21
article number
13190
pages
1 - 22
publisher
MDPI AG
external identifiers
  • pmid:36361981
  • scopus:85141647112
ISSN
1422-0067
DOI
10.3390/ijms232113190
language
English
LU publication?
yes
id
a71fc44e-1df0-48eb-89b8-6daa9bed0803
date added to LUP
2022-11-25 13:24:05
date last changed
2024-05-02 14:19:40
@article{a71fc44e-1df0-48eb-89b8-6daa9bed0803,
  abstract     = {{<p>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.</p>}},
  author       = {{Mikroulis, Apostolos and Waloschková, Eliška and Bengzon, Johan and Woldbye, David and Pinborg, Lars H and Jespersen, Bo and Avila, Anna Sanchez and Laszlo, Zsofia I and Henstridge, Christopher and Ledri, Marco and Kokaia, Merab}},
  issn         = {{1422-0067}},
  keywords     = {{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}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{21}},
  pages        = {{1--22}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{GDNF Increases Inhibitory Synaptic Drive on Principal Neurons in the Hippocampus via Activation of the Ret Pathway}},
  url          = {{http://dx.doi.org/10.3390/ijms232113190}},
  doi          = {{10.3390/ijms232113190}},
  volume       = {{23}},
  year         = {{2022}},
}