A transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex
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Evaluation Summary:
Homeostatic plasticity helps to confine neural network activity within limits. In this study, the authors show that loss of PAR bZIP family of transcription factors leads to overcompensation of excitatory synaptic transmission and average network activity upon sustained activity deprivation. The work identifies an endogenous transcriptional program that constrains upward homeostatic response and whose activity is implicated in preventing aberrant network activity associated with epilepsy and other brain disorders. These are exciting results that address the question of broad importance. While most arguments are supported by data of high quality, further experiments would strengthen the claims about the relative contribution of excitatory and inhibitory mechanisms and clarify the nature of compensation.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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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.
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Evaluation Summary:
Homeostatic plasticity helps to confine neural network activity within limits. In this study, the authors show that loss of PAR bZIP family of transcription factors leads to overcompensation of excitatory synaptic transmission and average network activity upon sustained activity deprivation. The work identifies an endogenous transcriptional program that constrains upward homeostatic response and whose activity is implicated in preventing aberrant network activity associated with epilepsy and other brain disorders. These are exciting results that address the question of broad importance. While most arguments are supported by data of high quality, further experiments would strengthen the claims about the relative contribution of excitatory and inhibitory mechanisms and clarify the nature of compensation.
(This preprint …
Evaluation Summary:
Homeostatic plasticity helps to confine neural network activity within limits. In this study, the authors show that loss of PAR bZIP family of transcription factors leads to overcompensation of excitatory synaptic transmission and average network activity upon sustained activity deprivation. The work identifies an endogenous transcriptional program that constrains upward homeostatic response and whose activity is implicated in preventing aberrant network activity associated with epilepsy and other brain disorders. These are exciting results that address the question of broad importance. While most arguments are supported by data of high quality, further experiments would strengthen the claims about the relative contribution of excitatory and inhibitory mechanisms and clarify the nature of compensation.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
Homeostatic plasticity is a process that helps to confine neural network activity within limits. While our understanding of the expression mechanisms of homeostatic plasticity have considerably advanced, very little is known of how the bounds of permissive activity levels are set and kept in check. In this study, the authors present data indicating that activation of PAR bZIP family of transcription factors help confine the extent of homeostatic synaptic plasticity, illustrating the existence of a negative regulator of homeostatic plasticity.
The study addresses a timely topic of general interest and the key findings are important. The data as presented leave some questions concerning the conclusion that Par bZIP proteins act as negative regulators of homeostatic synaptic plasticity. Although TTX treatment …
Reviewer #1 (Public Review):
Homeostatic plasticity is a process that helps to confine neural network activity within limits. While our understanding of the expression mechanisms of homeostatic plasticity have considerably advanced, very little is known of how the bounds of permissive activity levels are set and kept in check. In this study, the authors present data indicating that activation of PAR bZIP family of transcription factors help confine the extent of homeostatic synaptic plasticity, illustrating the existence of a negative regulator of homeostatic plasticity.
The study addresses a timely topic of general interest and the key findings are important. The data as presented leave some questions concerning the conclusion that Par bZIP proteins act as negative regulators of homeostatic synaptic plasticity. Although TTX treatment substantially increases the expression of both HLF and TEF, HLF is dramatically upregulated in PV+ neurons compared to pyramidal cells. In addition, when whole cortical lysates are examined, the kinetics of upregulation of HLF and TEF appear to differ. Given that slice cultures from mice lacking HLF, TEF and DBP show a strong reduction in mIPSC amplitude, which is otherwise compensated presumably via mechanisms independent of Par bZIP transcription factors, additional characterization of the expression properties and the respective roles of HLF and TEF in pyramidal and PV+ neurons might help provide a clearer view of when and how HLF and TEF are engaged to regulate network activity.
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Reviewer #2 (Public Review):
Valakh et al. report increased transcript abundance of PAR bZIP transcription factors after treating organotypic cortical mouse brain slice cultures with TTX for five days. Triple-knockout neurons lacking the transcription factors Hlf, Dbp and Tef displayed a more pronounced increase in calcium spike frequency and mEPSC frequency upon TTX treatment than controls, suggesting that these transcription factors limit homeostatic compensation. The study addresses a very interesting and almost completely unresolved question - the mechanisms that may constrain homeostatic plasticity. In principle, this paper presents highly relevant data for the field of synaptic transmission and synaptic plasticity.
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Reviewer #3 (Public Review):
The manuscript by Valakh et al. discovered transcription factors (TFs) belonging to the PAR bZIP family that normally limit upward homeostatic response without affecting baseline activity levels. The authors show that long-term blockade of spikes by TTX activates Hlf, Tef, and Dbp TFs in both excitatory and inhibitory neurons. The authors demonstrate that chronic silencing in TKO slice cultures that lack all 3 TFs causes over-compensation at the presynaptic level, reflected by larger increase in mEPSC frequency, but not at the postsynaptic level or at the level of intrinsic excitability in excitatory neurons. In addition, homeostatic plasticity of inhibitory synapses at excitatory neurons was disturbed by TKO. At the network level, over-compensation of average activity level was observed in TKO following …
Reviewer #3 (Public Review):
The manuscript by Valakh et al. discovered transcription factors (TFs) belonging to the PAR bZIP family that normally limit upward homeostatic response without affecting baseline activity levels. The authors show that long-term blockade of spikes by TTX activates Hlf, Tef, and Dbp TFs in both excitatory and inhibitory neurons. The authors demonstrate that chronic silencing in TKO slice cultures that lack all 3 TFs causes over-compensation at the presynaptic level, reflected by larger increase in mEPSC frequency, but not at the postsynaptic level or at the level of intrinsic excitability in excitatory neurons. In addition, homeostatic plasticity of inhibitory synapses at excitatory neurons was disturbed by TKO. At the network level, over-compensation of average activity level was observed in TKO following prolonged network silencing. In contrast, no deficits in downward homeostasis from hyperactive state were detected.
These are exciting results that demonstrate a novel transcriptional program that normally restricts upward homeostatic plasticity and prevents over-compensation. While previous studies revealed transcriptional regulation that enables downward firing rate homeostasis by REST (Pozzi et al., EMBO 2013), this work is the first one to identify transcriptional regulation that restricts upward firing rate homeostasis. Hlf, Tef, and Dbp TFs are regulated by circadian clock and may be implicated in many types of physiological regulations across light-dark phases. The knockout mice lacking all 3 TFs show epilepsy phenotype and short lifespan that can be related to a novel mechanism discovered by the authors. The paper is of high significance for both basic neuroscience and neuropathology related to homeostatic deficits, such as epilepsy, neuropsychiatric disorders and many more.
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