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Activin A Reduces GIRK Current to Excite Dentate Gyrus Granule Cells

Activin A, a member of the TGF-β family, is recognized as a multifunctional protein in the adult brain with a particular impact on neuronal circuits associated with cognitive and affective functions. Activin receptor signaling in mouse hippocampus is strongly enhanced by the exploration of an enrich...

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Autores principales: Zheng, Fang, Valero-Aracama, Maria Jesus, Schaefer, Natascha, Alzheimer, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9197229/
https://www.ncbi.nlm.nih.gov/pubmed/35711474
http://dx.doi.org/10.3389/fncel.2022.920388
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author Zheng, Fang
Valero-Aracama, Maria Jesus
Schaefer, Natascha
Alzheimer, Christian
author_facet Zheng, Fang
Valero-Aracama, Maria Jesus
Schaefer, Natascha
Alzheimer, Christian
author_sort Zheng, Fang
collection PubMed
description Activin A, a member of the TGF-β family, is recognized as a multifunctional protein in the adult brain with a particular impact on neuronal circuits associated with cognitive and affective functions. Activin receptor signaling in mouse hippocampus is strongly enhanced by the exploration of an enriched environment (EE), a behavioral paradigm known to improve performance in learning and memory tasks and to ameliorate depression-like behaviors. To interrogate the relationship between EE, activin signaling, and cellular excitability in the hippocampus, we performed ex vivo whole-cell recordings from dentate gyrus (DG) granule cells (GCs) of wild type mice and transgenic mice expressing a dominant-negative mutant of activin receptor IB (dnActRIB), which disrupts activin signaling in a forebrain-specific fashion. We found that, after overnight EE housing, GC excitability was strongly enhanced in an activin-dependent fashion. Moreover, the effect of EE on GC firing was mimicked by pre-treatment of hippocampal slices from control mice with recombinant activin A for several hours. The excitatory effect of activin A was preserved when canonical SMAD-dependent signaling was pharmacologically suppressed but was blocked by inhibitors of ERK-MAPK and PKA signaling. The involvement of a non-genomic signaling cascade was supported by the fact that the excitatory effect of activin A was already achieved within minutes of application. With respect to the ionic mechanism underlying the increase in intrinsic excitability, voltage-clamp recordings revealed that activin A induced an apparent inward current, which resulted from the suppression of a standing G protein-gated inwardly rectifying K(+) (GIRK) current. The link between EE, enhanced activin signaling, and inhibition of GIRK current was strengthened by the following findings: (i) The specific GIRK channel blocker tertiapin Q (TQ) occluded the characteristic electrophysiological effects of activin A in both current- and voltage-clamp recordings. (ii) The outward current evoked by the GIRK channel activator adenosine was significantly reduced by preceding EE exploration as well as by recombinant activin A in control slices. In conclusion, our study identifies GIRK current suppression via non-canonical activin signaling as a mechanism that might at least in part contribute to the beneficial effects of EE on cognitive performance and affective behavior.
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spelling pubmed-91972292022-06-15 Activin A Reduces GIRK Current to Excite Dentate Gyrus Granule Cells Zheng, Fang Valero-Aracama, Maria Jesus Schaefer, Natascha Alzheimer, Christian Front Cell Neurosci Cellular Neuroscience Activin A, a member of the TGF-β family, is recognized as a multifunctional protein in the adult brain with a particular impact on neuronal circuits associated with cognitive and affective functions. Activin receptor signaling in mouse hippocampus is strongly enhanced by the exploration of an enriched environment (EE), a behavioral paradigm known to improve performance in learning and memory tasks and to ameliorate depression-like behaviors. To interrogate the relationship between EE, activin signaling, and cellular excitability in the hippocampus, we performed ex vivo whole-cell recordings from dentate gyrus (DG) granule cells (GCs) of wild type mice and transgenic mice expressing a dominant-negative mutant of activin receptor IB (dnActRIB), which disrupts activin signaling in a forebrain-specific fashion. We found that, after overnight EE housing, GC excitability was strongly enhanced in an activin-dependent fashion. Moreover, the effect of EE on GC firing was mimicked by pre-treatment of hippocampal slices from control mice with recombinant activin A for several hours. The excitatory effect of activin A was preserved when canonical SMAD-dependent signaling was pharmacologically suppressed but was blocked by inhibitors of ERK-MAPK and PKA signaling. The involvement of a non-genomic signaling cascade was supported by the fact that the excitatory effect of activin A was already achieved within minutes of application. With respect to the ionic mechanism underlying the increase in intrinsic excitability, voltage-clamp recordings revealed that activin A induced an apparent inward current, which resulted from the suppression of a standing G protein-gated inwardly rectifying K(+) (GIRK) current. The link between EE, enhanced activin signaling, and inhibition of GIRK current was strengthened by the following findings: (i) The specific GIRK channel blocker tertiapin Q (TQ) occluded the characteristic electrophysiological effects of activin A in both current- and voltage-clamp recordings. (ii) The outward current evoked by the GIRK channel activator adenosine was significantly reduced by preceding EE exploration as well as by recombinant activin A in control slices. In conclusion, our study identifies GIRK current suppression via non-canonical activin signaling as a mechanism that might at least in part contribute to the beneficial effects of EE on cognitive performance and affective behavior. Frontiers Media S.A. 2022-05-27 /pmc/articles/PMC9197229/ /pubmed/35711474 http://dx.doi.org/10.3389/fncel.2022.920388 Text en Copyright © 2022 Zheng, Valero-Aracama, Schaefer and Alzheimer. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cellular Neuroscience
Zheng, Fang
Valero-Aracama, Maria Jesus
Schaefer, Natascha
Alzheimer, Christian
Activin A Reduces GIRK Current to Excite Dentate Gyrus Granule Cells
title Activin A Reduces GIRK Current to Excite Dentate Gyrus Granule Cells
title_full Activin A Reduces GIRK Current to Excite Dentate Gyrus Granule Cells
title_fullStr Activin A Reduces GIRK Current to Excite Dentate Gyrus Granule Cells
title_full_unstemmed Activin A Reduces GIRK Current to Excite Dentate Gyrus Granule Cells
title_short Activin A Reduces GIRK Current to Excite Dentate Gyrus Granule Cells
title_sort activin a reduces girk current to excite dentate gyrus granule cells
topic Cellular Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9197229/
https://www.ncbi.nlm.nih.gov/pubmed/35711474
http://dx.doi.org/10.3389/fncel.2022.920388
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