GDNF Increases Inhibitory Synaptic Drive on Principal Neurons in the Hippocampus via Activation of the Ret Pathway
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GDNF Increases Inhibitory Synaptic Drive on Principal Neurons in the Hippocampus via Activation of the Ret Pathway. / Mikroulis, Apostolos; Waloschková, Eliška; Bengzon, Johan; Woldbye, David; Pinborg, Lars H.; Jespersen, Bo; Avila, Anna Sanchez; Laszlo, Zsofia I.; Henstridge, Christopher; Ledri, Marco; Kokaia, Merab.
In: International Journal of Molecular Sciences, Vol. 23, No. 21, 13190, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - GDNF Increases Inhibitory Synaptic Drive on Principal Neurons in the Hippocampus via Activation of the Ret Pathway
AU - Mikroulis, Apostolos
AU - Waloschková, Eliška
AU - Bengzon, Johan
AU - Woldbye, David
AU - Pinborg, Lars H.
AU - Jespersen, Bo
AU - Avila, Anna Sanchez
AU - Laszlo, Zsofia I.
AU - Henstridge, Christopher
AU - Ledri, Marco
AU - Kokaia, Merab
N1 - Publisher Copyright: © 2022 by the authors.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - electrophysiology
KW - epilepsy
KW - GDNF
KW - IPSC
KW - ret
U2 - 10.3390/ijms232113190
DO - 10.3390/ijms232113190
M3 - Journal article
C2 - 36361981
AN - SCOPUS:85141647112
VL - 23
JO - International Journal of Molecular Sciences (Online)
JF - International Journal of Molecular Sciences (Online)
SN - 1661-6596
IS - 21
M1 - 13190
ER -
ID: 326841396