Cargando…
A transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex
Healthy neuronal networks rely on homeostatic plasticity to maintain stable firing rates despite changing synaptic drive. These mechanisms, however, can themselves be destabilizing if activated inappropriately or excessively. For example, prolonged activity deprivation can lead to rebound hyperactiv...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10010687/ https://www.ncbi.nlm.nih.gov/pubmed/36749029 http://dx.doi.org/10.7554/eLife.74899 |
_version_ | 1784906224553164800 |
---|---|
author | Valakh, Vera Wise, Derek Zhu, Xiaoyue Aelita Sha, Mingqi Fok, Jaidyn Van Hooser, Stephen D Schectman, Robin Cepeda, Isabel Kirk, Ryan O'Toole, Sean M Nelson, Sacha B |
author_facet | Valakh, Vera Wise, Derek Zhu, Xiaoyue Aelita Sha, Mingqi Fok, Jaidyn Van Hooser, Stephen D Schectman, Robin Cepeda, Isabel Kirk, Ryan O'Toole, Sean M Nelson, Sacha B |
author_sort | Valakh, Vera |
collection | PubMed |
description | Healthy neuronal networks rely on homeostatic plasticity to maintain stable firing rates despite changing synaptic drive. These mechanisms, however, can themselves be destabilizing if activated inappropriately or excessively. For example, prolonged activity deprivation can lead to rebound hyperactivity and seizures. While many forms of homeostasis have been described, whether and how the magnitude of homeostatic plasticity is constrained remains unknown. Here, we uncover negative regulation of cortical network homeostasis by the PARbZIP family of transcription factors. In cortical slice cultures made from knockout mice lacking all three of these factors, the network response to prolonged activity withdrawal measured with calcium imaging is much stronger, while baseline activity is unchanged. Whole-cell recordings reveal an exaggerated increase in the frequency of miniature excitatory synaptic currents reflecting enhanced upregulation of recurrent excitatory synaptic transmission. Genetic analyses reveal that two of the factors, Hlf and Tef, are critical for constraining plasticity and for preventing life-threatening seizures. These data indicate that transcriptional activation is not only required for many forms of homeostatic plasticity but is also involved in restraint of the response to activity deprivation. |
format | Online Article Text |
id | pubmed-10010687 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-100106872023-03-14 A transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex Valakh, Vera Wise, Derek Zhu, Xiaoyue Aelita Sha, Mingqi Fok, Jaidyn Van Hooser, Stephen D Schectman, Robin Cepeda, Isabel Kirk, Ryan O'Toole, Sean M Nelson, Sacha B eLife Neuroscience Healthy neuronal networks rely on homeostatic plasticity to maintain stable firing rates despite changing synaptic drive. These mechanisms, however, can themselves be destabilizing if activated inappropriately or excessively. For example, prolonged activity deprivation can lead to rebound hyperactivity and seizures. While many forms of homeostasis have been described, whether and how the magnitude of homeostatic plasticity is constrained remains unknown. Here, we uncover negative regulation of cortical network homeostasis by the PARbZIP family of transcription factors. In cortical slice cultures made from knockout mice lacking all three of these factors, the network response to prolonged activity withdrawal measured with calcium imaging is much stronger, while baseline activity is unchanged. Whole-cell recordings reveal an exaggerated increase in the frequency of miniature excitatory synaptic currents reflecting enhanced upregulation of recurrent excitatory synaptic transmission. Genetic analyses reveal that two of the factors, Hlf and Tef, are critical for constraining plasticity and for preventing life-threatening seizures. These data indicate that transcriptional activation is not only required for many forms of homeostatic plasticity but is also involved in restraint of the response to activity deprivation. eLife Sciences Publications, Ltd 2023-02-07 /pmc/articles/PMC10010687/ /pubmed/36749029 http://dx.doi.org/10.7554/eLife.74899 Text en © 2023, Valakh et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Neuroscience Valakh, Vera Wise, Derek Zhu, Xiaoyue Aelita Sha, Mingqi Fok, Jaidyn Van Hooser, Stephen D Schectman, Robin Cepeda, Isabel Kirk, Ryan O'Toole, Sean M Nelson, Sacha B A transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex |
title | A transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex |
title_full | A transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex |
title_fullStr | A transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex |
title_full_unstemmed | A transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex |
title_short | A transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex |
title_sort | transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10010687/ https://www.ncbi.nlm.nih.gov/pubmed/36749029 http://dx.doi.org/10.7554/eLife.74899 |
work_keys_str_mv | AT valakhvera atranscriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT wisederek atranscriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT zhuxiaoyueaelita atranscriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT shamingqi atranscriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT fokjaidyn atranscriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT vanhooserstephend atranscriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT schectmanrobin atranscriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT cepedaisabel atranscriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT kirkryan atranscriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT otooleseanm atranscriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT nelsonsachab atranscriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT valakhvera transcriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT wisederek transcriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT zhuxiaoyueaelita transcriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT shamingqi transcriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT fokjaidyn transcriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT vanhooserstephend transcriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT schectmanrobin transcriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT cepedaisabel transcriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT kirkryan transcriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT otooleseanm transcriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex AT nelsonsachab transcriptionalconstraintmechanismlimitsthehomeostaticresponsetoactivitydeprivationinmammalianneocortex |