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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| Format: | Article |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2022.920388/full |
| _version_ | 1828200763403272192 |
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| author | Fang Zheng Maria Jesus Valero-Aracama Natascha Schaefer Christian Alzheimer |
| author_facet | Fang Zheng Maria Jesus Valero-Aracama Natascha Schaefer Christian Alzheimer |
| author_sort | Fang Zheng |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T11:19:27Z |
| format | Article |
| id | doaj.art-cca7e8f295f240aa87dc760b82431910 |
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| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-04-12T11:19:27Z |
| publishDate | 2022-05-01 |
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| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-cca7e8f295f240aa87dc760b824319102022-12-22T03:35:25ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022022-05-011610.3389/fncel.2022.920388920388Activin A Reduces GIRK Current to Excite Dentate Gyrus Granule CellsFang Zheng0Maria Jesus Valero-Aracama1Natascha Schaefer2Christian Alzheimer3Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität, Erlangen-Nürnberg, Erlangen, GermanyInstitute of Physiology and Pathophysiology, Friedrich-Alexander-Universität, Erlangen-Nürnberg, Erlangen, GermanyInstitute for Clinical Neurobiology, Julius-Maximilians-Universität Würzburg, Würzburg, GermanyInstitute of Physiology and Pathophysiology, Friedrich-Alexander-Universität, Erlangen-Nürnberg, Erlangen, GermanyActivin 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.https://www.frontiersin.org/articles/10.3389/fncel.2022.920388/fullactivinhippocampusGIRK currentaction potentialdentate gyrus granule cells |
| spellingShingle | Fang Zheng Maria Jesus Valero-Aracama Natascha Schaefer Christian Alzheimer Activin A Reduces GIRK Current to Excite Dentate Gyrus Granule Cells Frontiers in Cellular Neuroscience activin hippocampus GIRK current action potential 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 | activin hippocampus GIRK current action potential dentate gyrus granule cells |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2022.920388/full |
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