A transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex
- Brandeis University, United States
Abstract
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.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files, calcium imaging analysis code is available http://github.com/VH-Lab/vhlab-TwoPhoton-matlab. RNAseq data have been deposited to the BioSample database.
Article and author information
Author details
Stephen D Van Hooser
Funding
National Institute of Neurological Disorders and Stroke (R01NS109916)
- Sacha B Nelson
Simons Foundation Autism Research Initiative (648651)
- Sacha B Nelson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All procedures were approved by the Institutional Animal Care and Use Committee at Brandeis University (Protocol #20002), and conformed to the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
Copyright
© 2023, Valakh et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex
eLife 12:e74899.
https://doi.org/10.7554/eLife.74899
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