Functional characterization of GABAA receptor-mediated modulation of cortical neuron network activity in microelectrode array recordings
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Functional characterization of GABAA receptor-mediated modulation of cortical neuron network activity in microelectrode array recordings. / Bader, Benjamin M; Steder, Anne; Klein, Anders Bue; Frølund, Bente; Schroeder, Olaf H U; Jensen, Anders A.
In: PloS One, Vol. 12, No. 10, e0186147, 2017.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Functional characterization of GABAA receptor-mediated modulation of cortical neuron network activity in microelectrode array recordings
AU - Bader, Benjamin M
AU - Steder, Anne
AU - Klein, Anders Bue
AU - Frølund, Bente
AU - Schroeder, Olaf H U
AU - Jensen, Anders A
PY - 2017
Y1 - 2017
N2 - The numerous γ-aminobutyric acid type A receptor (GABAAR) subtypes are differentially expressed and mediate distinct functions at neuronal level. In this study we have investigated GABAAR-mediated modulation of the spontaneous activity patterns of primary neuronal networks from murine frontal cortex by characterizing the effects induced by a wide selection of pharmacological tools at a plethora of activity parameters in microelectrode array (MEA) recordings. The basic characteristics of the primary cortical neurons used in the recordings were studied in some detail, and the expression levels of various GABAAR subunits were investigated by western blotting and RT-qPCR. In the MEA recordings, the pan-GABAAR agonist muscimol and the GABABR agonist baclofen were observed to mediate phenotypically distinct changes in cortical network activity. Selective augmentation of αβγ GABAAR signaling by diazepam and of δ-containing GABAAR (δ-GABAAR) signaling by DS1 produced pronounced changes in the majority of the activity parameters, both drugs mediating similar patterns of activity changes as muscimol. The apparent importance of δ-GABAAR signaling for network activity was largely corroborated by the effects induced by the functionally selective δ-GABAAR agonists THIP and Thio-THIP, whereas the δ-GABAAR selective potentiator DS2 only mediated modest effects on network activity, even when co-applied with low THIP concentrations. Interestingly, diazepam exhibited dramatically right-shifted concentration-response relationships at many of the activity parameters when co-applied with a trace concentration of DS1 compared to when applied alone. In contrast, the potencies and efficacies displayed by DS1 at the networks were not substantially altered by the concomitant presence of diazepam. In conclusion, the holistic nature of the information extractable from the MEA recordings offers interesting insights into the contributions of various GABAAR subtypes/subgroups to cortical network activity and the putative functional interplay between these receptors in these neurons.
AB - The numerous γ-aminobutyric acid type A receptor (GABAAR) subtypes are differentially expressed and mediate distinct functions at neuronal level. In this study we have investigated GABAAR-mediated modulation of the spontaneous activity patterns of primary neuronal networks from murine frontal cortex by characterizing the effects induced by a wide selection of pharmacological tools at a plethora of activity parameters in microelectrode array (MEA) recordings. The basic characteristics of the primary cortical neurons used in the recordings were studied in some detail, and the expression levels of various GABAAR subunits were investigated by western blotting and RT-qPCR. In the MEA recordings, the pan-GABAAR agonist muscimol and the GABABR agonist baclofen were observed to mediate phenotypically distinct changes in cortical network activity. Selective augmentation of αβγ GABAAR signaling by diazepam and of δ-containing GABAAR (δ-GABAAR) signaling by DS1 produced pronounced changes in the majority of the activity parameters, both drugs mediating similar patterns of activity changes as muscimol. The apparent importance of δ-GABAAR signaling for network activity was largely corroborated by the effects induced by the functionally selective δ-GABAAR agonists THIP and Thio-THIP, whereas the δ-GABAAR selective potentiator DS2 only mediated modest effects on network activity, even when co-applied with low THIP concentrations. Interestingly, diazepam exhibited dramatically right-shifted concentration-response relationships at many of the activity parameters when co-applied with a trace concentration of DS1 compared to when applied alone. In contrast, the potencies and efficacies displayed by DS1 at the networks were not substantially altered by the concomitant presence of diazepam. In conclusion, the holistic nature of the information extractable from the MEA recordings offers interesting insights into the contributions of various GABAAR subtypes/subgroups to cortical network activity and the putative functional interplay between these receptors in these neurons.
KW - Allosteric Regulation
KW - Animals
KW - Drug Interactions
KW - Frontal Lobe
KW - GABA-A Receptor Agonists
KW - Mice
KW - Microelectrodes
KW - Neurons
KW - Receptors, GABA-A
KW - Journal Article
U2 - 10.1371/journal.pone.0186147
DO - 10.1371/journal.pone.0186147
M3 - Journal article
C2 - 29028808
VL - 12
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 10
M1 - e0186147
ER -
ID: 185654310