Firing Rate Homeostasis Can Occur in the Absence of Neuronal Activity-Regulated Transcription

Tyssowski, Kelsey M.; Letai, Katherine C; Rendall, Samuel D.; Tan, Chung-I; Nizhnik, Anastasia; Kaeser, Pascal S.; Gray, Jesse

doi:10.1523/jneurosci.1108-19.2019

Cited by 12 publications

(10 citation statements)

References 56 publications

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“…A hypothesis was tested that the activity dependent transcription necessary for supporting constant activity level (neuronal activity homeostasis); however, homeostasis was observed also in the neurons with the suppressed activity of the plasticity related gene Arc and in the absence of the activity dependent tran scription factors AP1 and SRF. The authors concluded that the activity regulated transcription was not necessary for the constantly maintained activity of the neuron [38].…”

Section: Specificity Of Epigenetic Regulation Of the Plasticity Relatmentioning

confidence: 99%

“…Stability of the spontaneous activity of neurons was analyzed in a very interesting work on a culture of mouse cortical neurons [38]. A hypothesis was tested that the activity dependent transcription necessary for supporting constant activity level (neuronal activity homeostasis); however, homeostasis was observed also in the neurons with the suppressed activity of the plasticity related gene Arc and in the absence of the activity dependent tran scription factors AP1 and SRF.…”

Section: Specificity Of Epigenetic Regulation Of the Plasticity Relatmentioning

confidence: 99%

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Epigenetic Regulation as a Basis for Long-Term Changes in the Nervous System: In Search of Specificity Mechanisms

Borodinova

Balaban

2020

Biochemistry Moscow

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Adaptive long-term changes in the functioning of nervous system (plasticity, memory) are not written in the genome, but are directly associated with the changes in expression of many genes comprising epigenetic regulation. Summarizing the known data regarding the role of epigenetics in regulation of plasticity and memory, we would like to highlight several key aspects. (i) Different chromatin remodeling complexes and DNA methyltransferases can be organized into high-order multiprotein repressor complexes that are cooperatively acting as the “molecular brake pads”, selectively restricting transcriptional activity of specific genes at rest. (ii) Relevant physiological stimuli induce a cascade of biochemical events in the activated neurons resulting in translocation of different signaling molecules (protein kinases, NO-containing complexes) to the nucleus. (iii) Stimulus-specific nitrosylation and phosphorylation of different epigenetic factors is linked to a decrease in their enzymatic activity or changes in intracellular localization that results in temporary destabilization of the repressor complexes. (iv) Removing “molecular brakes” opens a “critical time window” for global and local epigenetic changes, triggering specific transcriptional programs and modulation of synaptic connections efficiency. It can be assumed that the reversible post-translational histone modifications serve as the basis of plastic changes in the neural network. On the other hand, DNA methylation and methylation-dependent 3D chromatin organization can serve a stable molecular basis for long-term maintenance of plastic changes and memory.

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Section: Specificity Of Epigenetic Regulation Of the Plasticity Relatmentioning

confidence: 99%

Section: Specificity Of Epigenetic Regulation Of the Plasticity Relatmentioning

confidence: 99%

Epigenetic Regulation as a Basis for Long-Term Changes in the Nervous System: In Search of Specificity Mechanisms

Borodinova

Balaban

2020

Biochemistry Moscow

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“…For instance, the MFR of a neuronal population gradually renormalizes despite the constant presence of a pharmacological, genetic, or experiencedependent perturbation that initially caused a rapid change in MFR (Figure 1B,C). This process dubbed 'firing rate homeostasis,' occurs robustly in cultured neural networks ex vivo [9][10][11][12][13][14], and has been documented in vivo as well, such as in the rodent primary visual cortex (V1) [15][16][17]. On the basis of these results, MFR can be classified as a physiological variable that undergoes homeostatic set-point regulation.…”

Section: Homeostatic Regulation Of Firing Rate Set Pointsmentioning

confidence: 97%

“…Somatic mitochondria may regulate transcription [59], which is required for synaptic scaling [55]. However, a recent study suggests that transcription is not required for MFR renormalization, at least for Type 1 perturbations related to hyperactivity [14]. Future studies are needed to address whether transcription is unnecessary for inactivity perturbations as well and to understand the role of mitoCa 2+ -transcription coupling in homeostatic regulation.…”

Section: Sleep Homeostasismentioning

confidence: 99%

Mitochondria: new players in homeostatic regulation of firing rate set points

Ruggiero

Katsenelson

Slutsky

2021

Trends in Neurosciences

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Neural circuit functions are stabilized by homeostatic processes at long timescales in response to changes in behavioral states, experience, and learning. However, it remains unclear which specific physiological variables are being stabilized and which cellular or neural network components compose the homeostatic machinery. At this point, most evidence suggests that the distribution of firing rates among neurons in a neuronal circuit is the key variable that is maintained around a set-point value in a process called 'firing rate homeostasis.' Here, we review recent findings that implicate mitochondria as central players in mediating firing rate homeostasis. While mitochondria are known to regulate neuronal variables such as synaptic vesicle release or intracellular calcium concentration, the mitochondrial signaling pathways that are essential for firing rate homeostasis remain largely unknown. We used basic concepts of control theory to build a framework for classifying possible components of the homeostatic machinery that stabilizes firing rate, and we particularly emphasize the potential role of sleep and wakefulness in this homeostatic process. This framework may facilitate the identification of new homeostatic pathways whose malfunctions drive instability of neural circuits in distinct brain disorders. The concept of neuronal homeostasisThe concept of homeostasis, based on the classical works of Claude Bernard, Walter Cannon, and James Hardy, refers to the mechanisms that maintain physiological variables within a dynamic range around a 'set point' [1][2][3]. In the context of neural circuits, homeostatic negative feedbacks enable stable activity of neural networks over long timescales, despite the highly dynamic and heterogeneous nature of individual synapses and neurons. Without such homeostatic feedback, the circuit's function may be destabilized by Hebbian-like synaptic plasticity underlying the cellular basis of learning and memory [4,5]. This plasticity-stability problem has been introduced and elegantly reviewed in earlier insightful papers [6][7][8], but many key questions remain unanswered.In particular, what are the components of the core homeostatic machinery at the subcellular and neural network levels, and what variable(s) do they regulate to prevent aberrant long-term changes in neural network activity?The function of many cellular variables such as synaptic weights, ion channels, neurotransmitter release, and receptor expression are dynamic under normal conditions, and scientists are challenged to dissect which of these dynamics are homeostatic in nature. Application of engineering control theory [7] can be used to navigate this issue, based on the following principal characteristics: (i) a set point that the system must return to following a perturbation, which defines the output of the homeostatic machinery; (ii) sensors that detect deviation from that set point; and (iii) homeostatic effectors that precisely retarget some regulated variable to that set point via negative feedback (Figure 1A)....

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“…We are only beginning to understand the molecular mechanisms behind these changes. Even fundamental biological phenomena such as the adaptation in electrical excitability in response to the changing synaptic inputs are only beginning to be unraveled [106]. Cellular and animal models of dopamine depletion will be critical to address these questions and hold great promise to develop new non-dopaminergic therapies that have the potential to avoid these long-term consequences of dopamine depletion and substitution.…”

Section: Future Perspectives For Translational Researchmentioning

confidence: 99%

Parkinson’s disease and translational research

Dinter¹,

Saridaki²,

Diederichs³

et al. 2020

Transl Neurodegener

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Parkinson’s disease (PD) is diagnosed when patients exhibit bradykinesia with tremor and/or rigidity, and when these symptoms respond to dopaminergic medications. Yet in the last years there was a greater recognition of additional aspects of the disease including non-motor symptoms and prodromal states with associated pathology in various regions of the nervous system. In this review we discuss current concepts of two major alterations found during the course of the disease: cytoplasmic aggregates of the protein α-synuclein and the degeneration of dopaminergic neurons. We provide an overview of new approaches in this field based on current concepts and latest literature. In many areas, translational research on PD has advanced the understanding of the disease but there is still a need for more effective therapeutic options based on the insights into the basic biological phenomena.

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Firing Rate Homeostasis Can Occur in the Absence of Neuronal Activity-Regulated Transcription

Cited by 12 publications

References 56 publications

Epigenetic Regulation as a Basis for Long-Term Changes in the Nervous System: In Search of Specificity Mechanisms

Epigenetic Regulation as a Basis for Long-Term Changes in the Nervous System: In Search of Specificity Mechanisms

Mitochondria: new players in homeostatic regulation of firing rate set points

Parkinson’s disease and translational research

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