GDNF Increases Inhibitory Synaptic Drive on Principal Neurons in the Hippocampus via Activation of the Ret Pathway
(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.
(Less)
- author
- organization
- publishing date
- 2022-10-29
- 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
-
- scopus:85141647112
- pmid:36361981
- 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
- 2024-09-20 03:33:04
@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}}, }