Gutenberg Open Science: Tonic activation of GABAB receptors via GAT-3 mediated GABA release reduces network activity in the developing somatosensory cortex in GAD67-GFP mice

Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-9349

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DC Field	Value	Language
dc.contributor.author	Ueberbach, Timo	-
dc.contributor.author	Simacek, Clara A.	-
dc.contributor.author	Tegeder, Irmgard	-
dc.contributor.author	Kirischuk, Sergei	-
dc.contributor.author	Mittmann, Thomas	-
dc.date.accessioned	2023-08-08T07:16:19Z	-
dc.date.available	2023-08-08T07:16:19Z	-
dc.date.issued	2023	-
dc.identifier.uri	https://openscience.ub.uni-mainz.de/handle/20.500.12030/9367	-
dc.description.abstract	The efficiency of neocortical information processing critically depends on the balance between the glutamatergic (excitatory, E) and GABAergic (inhibitory, I) synaptic transmission. A transient imbalance of the E/I-ratio during early development might lead to neuropsychiatric disorders later in life. The transgenic glutamic acid decarboxylase 67-green fluorescent protein (GAD67-GFP) mouse line (KI) was developed to selectively visualize GABAergic interneurons in the CNS. However, haplodeficiency of the GAD67 enzyme, the main GABA synthetizing enzyme in the brain, temporarily leads to a low GABA level in the developing brain of these animals. However, KI mice did not demonstrate any epileptic activity and only few and mild behavioral deficits. In the present study we investigated how the developing somatosensory cortex of KI-mice compensates the reduced GABA level to prevent brain hyperexcitability. Whole-cell patch clamp recordings from layer 2/3 pyramidal neurons at P14 and at P21 revealed a reduced frequency of miniature inhibitory postsynaptic currents (mIPSCs) in KI mice without any change in amplitude or kinetics. Interestingly, mEPSC frequencies were also decreased, while the E/I-ratio was nevertheless shifted toward excitation. Surprisingly, multi-electrode-recordings (MEA) from acute slices revealed a decreased spontaneous neuronal network activity in KI mice compared to wild-type (WT) littermates, pointing to a compensatory mechanism that prevents hyperexcitability. Blockade of GABAB receptors (GABABRs) with CGP55845 strongly increased the frequency of mEPSCs in KI, but failed to affect mIPSCs in any genotype or age. It also induced a membrane depolarization in P14 KI, but not in P21 KI or WT mice. MEA recordings in presence of CGP55845 revealed comparable levels of network activity in both genotypes, indicating that tonically activated GABABRs balance neuronal activity in P14 KI cortex despite the reduced GABA levels. Blockade of GABA transporter 3 (GAT-3) reproduced the CGP55845 effects suggesting that tonic activation of GABABRs is mediated by ambient GABA released via GAT-3 operating in reverse mode. We conclude that GAT-3-mediated GABA release leads to tonic activation of both pre- and postsynaptic GABABRs and restricts neuronal excitability in the developing cortex to compensate for reduced neuronal GABA synthesis. Since GAT-3 is predominantly located in astrocytes, GAD67 haplodeficiency may potentially stimulate astrocytic GABA synthesis through GAD67-independent pathways.	en_GB
dc.description.sponsorship	Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 491381577	de
dc.language.iso	eng	de
dc.rights	CC BY	*
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/	*
dc.subject.ddc	610 Medizin	de_DE
dc.subject.ddc	610 Medical sciences	en_GB
dc.title	Tonic activation of GABAB receptors via GAT-3 mediated GABA release reduces network activity in the developing somatosensory cortex in GAD67-GFP mice	en_GB
dc.type	Zeitschriftenaufsatz	de
dc.identifier.doi	http://doi.org/10.25358/openscience-9349	-
jgu.type.contenttype	Scientific article	de
jgu.type.dinitype	article	en_GB
jgu.type.version	Published version	de
jgu.type.resource	Text	de
jgu.organisation.department	FB 04 Medizin	de
jgu.organisation.number	2700	-
jgu.organisation.name	Johannes Gutenberg-Universität Mainz	-
jgu.rights.accessrights	openAccess	-
jgu.journal.title	Frontiers in synaptic neuroscience	de
jgu.journal.volume	15	de
jgu.pages.alternative	1198159	de
jgu.publisher.year	2023	-
jgu.publisher.name	Frontiers Research Foundation	de
jgu.publisher.place	Lausanne	de
jgu.publisher.issn	1663-3563	de
jgu.organisation.place	Mainz	-
jgu.subject.ddccode	610	de
jgu.publisher.doi	10.3389/fnsyn.2023.1198159	de
jgu.organisation.ror	https://ror.org/023b0x485	-
jgu.subject.dfg	Naturwissenschaften	de
Appears in collections:	DFG-491381577-G

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