REST/NRSF drives homeostatic plasticity of inhibitory synapses in a target-dependent fashion
The repressor-element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF) controls hundreds of neuron-specific genes. We showed that REST/NRSF downregulates glutamatergic transmission in response to hyperactivity, thus contributing to neuronal homeostasis. However, whether GABAe...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/69058 |
| _version_ | 1811180394262822912 |
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| author | Cosimo Prestigio Daniele Ferrante Antonella Marte Alessandra Romei Gabriele Lignani Franco Onofri Pierluigi Valente Fabio Benfenati Pietro Baldelli |
| author_facet | Cosimo Prestigio Daniele Ferrante Antonella Marte Alessandra Romei Gabriele Lignani Franco Onofri Pierluigi Valente Fabio Benfenati Pietro Baldelli |
| author_sort | Cosimo Prestigio |
| collection | DOAJ |
| description | The repressor-element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF) controls hundreds of neuron-specific genes. We showed that REST/NRSF downregulates glutamatergic transmission in response to hyperactivity, thus contributing to neuronal homeostasis. However, whether GABAergic transmission is also implicated in the homeostatic action of REST/NRSF is unknown. Here, we show that hyperactivity-induced REST/NRSF activation, triggers a homeostatic rearrangement of GABAergic inhibition, with increased frequency of miniature inhibitory postsynaptic currents (IPSCs) and amplitude of evoked IPSCs in mouse cultured hippocampal neurons. Notably, this effect is limited to inhibitory-onto-excitatory neuron synapses, whose density increases at somatic level and decreases in dendritic regions, demonstrating a complex target- and area-selectivity. The upscaling of perisomatic inhibition was occluded by TrkB receptor inhibition and resulted from a coordinated and sequential activation of the Npas4 and Bdnf gene programs. On the opposite, the downscaling of dendritic inhibition was REST-dependent, but BDNF-independent. The findings highlight the central role of REST/NRSF in the complex transcriptional responses aimed at rescuing physiological levels of network activity in front of the ever-changing environment. |
| first_indexed | 2024-04-11T09:01:20Z |
| format | Article |
| id | doaj.art-14914593879644449fe8f7f3e92e6cdc |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:01:20Z |
| publishDate | 2021-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-14914593879644449fe8f7f3e92e6cdc2022-12-22T04:32:45ZengeLife Sciences Publications LtdeLife2050-084X2021-12-011010.7554/eLife.69058REST/NRSF drives homeostatic plasticity of inhibitory synapses in a target-dependent fashionCosimo Prestigio0Daniele Ferrante1Antonella Marte2Alessandra Romei3Gabriele Lignani4https://orcid.org/0000-0002-3963-9296Franco Onofri5Pierluigi Valente6Fabio Benfenati7https://orcid.org/0000-0002-0653-8368Pietro Baldelli8https://orcid.org/0000-0001-9599-3436Department of Experimental Medicine, University of Genova, Genova, Italy; Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, ItalyDepartment of Experimental Medicine, University of Genova, Genova, Italy; Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, ItalyDepartment of Experimental Medicine, University of Genova, Genova, ItalyCenter for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, ItalyDepartment of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, Queen Square House, London, United KingdomDepartment of Experimental Medicine, University of Genova, Genova, Italy; IRCCS, Ospedale Policlinico San Martino, Genova, ItalyDepartment of Experimental Medicine, University of Genova, Genova, Italy; IRCCS, Ospedale Policlinico San Martino, Genova, ItalyCenter for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, Italy; IRCCS, Ospedale Policlinico San Martino, Genova, ItalyDepartment of Experimental Medicine, University of Genova, Genova, Italy; IRCCS, Ospedale Policlinico San Martino, Genova, ItalyThe repressor-element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF) controls hundreds of neuron-specific genes. We showed that REST/NRSF downregulates glutamatergic transmission in response to hyperactivity, thus contributing to neuronal homeostasis. However, whether GABAergic transmission is also implicated in the homeostatic action of REST/NRSF is unknown. Here, we show that hyperactivity-induced REST/NRSF activation, triggers a homeostatic rearrangement of GABAergic inhibition, with increased frequency of miniature inhibitory postsynaptic currents (IPSCs) and amplitude of evoked IPSCs in mouse cultured hippocampal neurons. Notably, this effect is limited to inhibitory-onto-excitatory neuron synapses, whose density increases at somatic level and decreases in dendritic regions, demonstrating a complex target- and area-selectivity. The upscaling of perisomatic inhibition was occluded by TrkB receptor inhibition and resulted from a coordinated and sequential activation of the Npas4 and Bdnf gene programs. On the opposite, the downscaling of dendritic inhibition was REST-dependent, but BDNF-independent. The findings highlight the central role of REST/NRSF in the complex transcriptional responses aimed at rescuing physiological levels of network activity in front of the ever-changing environment.https://elifesciences.org/articles/69058REST/NRSFGABAergic synapsesBDNFsynaptic homeostasisneural hyperactivityhomeostatic plasticity |
| spellingShingle | Cosimo Prestigio Daniele Ferrante Antonella Marte Alessandra Romei Gabriele Lignani Franco Onofri Pierluigi Valente Fabio Benfenati Pietro Baldelli REST/NRSF drives homeostatic plasticity of inhibitory synapses in a target-dependent fashion eLife REST/NRSF GABAergic synapses BDNF synaptic homeostasis neural hyperactivity homeostatic plasticity |
| title | REST/NRSF drives homeostatic plasticity of inhibitory synapses in a target-dependent fashion |
| title_full | REST/NRSF drives homeostatic plasticity of inhibitory synapses in a target-dependent fashion |
| title_fullStr | REST/NRSF drives homeostatic plasticity of inhibitory synapses in a target-dependent fashion |
| title_full_unstemmed | REST/NRSF drives homeostatic plasticity of inhibitory synapses in a target-dependent fashion |
| title_short | REST/NRSF drives homeostatic plasticity of inhibitory synapses in a target-dependent fashion |
| title_sort | rest nrsf drives homeostatic plasticity of inhibitory synapses in a target dependent fashion |
| topic | REST/NRSF GABAergic synapses BDNF synaptic homeostasis neural hyperactivity homeostatic plasticity |
| url | https://elifesciences.org/articles/69058 |
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