Circadian Regulation of Endoplasmic Reticulum Calcium Signaling in Mouse Astrocytes

Core Concepts

The circadian clock controls rhythmic expression of the ER protein HERP, which regulates inositol 1,4,5-trisphosphate receptor (IP3R) levels and modulates ATP-induced endoplasmic reticulum (ER) calcium release in mouse astrocytes. This circadian variation in ER calcium signaling leads to day/night differences in astrocytic gap junction communication.

Abstract

The study investigated how the circadian clock regulates astrocyte function using a circadian transcriptome analysis of mouse cultured cortical astrocytes. The analysis identified 412 circadian rhythmic transcripts, including the gene Herp, which encodes the ER protein HERP. HERP exhibited robust circadian rhythmicity at both mRNA and protein levels in a BMAL1-dependent manner.
HERP was found to regulate ER calcium release by modulating the degradation of inositol 1,4,5-trisphosphate receptors (IP3Rs). ATP-stimulated ER calcium release varied according to circadian time (CT), being more pronounced during the subjective night. This rhythmic ER calcium response led to day/night variations in the phosphorylation of the gap junction protein Connexin 43 (CX43) at Ser368, likely diminishing cell-to-cell communication between astrocytes during the active phase.
The study suggests that the circadian clock orchestrates astrocytic processes, including calcium homeostasis, by controlling the rhythmic transcription of genes. This circadian regulation of ER calcium signaling and gap junction communication could influence astrocytic modulation of synaptic activity according to the time of day.

Stats

Herp mRNA levels exhibited a circadian rhythm with a peak at CT12.
HERP protein levels oscillated, peaking at midday (CT10, CT34) and reaching a minimum early in the day or late at night (CT4, CT22, CT36).
ATP treatment rapidly decreased ER calcium in control astrocytes, and this response was greater in Herp siRNA-treated astrocytes.
ATP-induced phosphorylation of Cx43 at Ser368 was significantly higher at CT22 compared to CT34.

Quotes

"Herp was first identified as a novel gene that exhibited altered expression in response to homocysteine treatment in human umbilical vein endothelial cells (HUVECs) as part of a study on hyperhomocysteinemia."
"HERP, characterized by an N-terminal ubiquitin-like domain and present in the ER membrane, facing cytoplasmic side, has emerged as a novel target protein in the unfolded protein response (UPR)."
"Notably, a recent study reported that HERP is capable of modulating the ER Ca2+ response through IP3R degradation."

Key Insights Distilled From

Circadian regulation of endoplasmic reticulum calcium response in mouse cultured astrocytes

by Ryu,J. E., S... at www.biorxiv.org 02-04-2024

https://www.biorxiv.org/content/10.1101/2024.02.02.578616v2

Deeper Inquiries

How might the circadian regulation of astrocytic calcium signaling and gap junction communication impact neuronal function and behavior in vivo?

The circadian regulation of astrocytic calcium signaling and gap junction communication can have profound effects on neuronal function and behavior in vivo. Astrocytes play a crucial role in modulating synaptic activity through the release of gliotransmitters in response to changes in intracellular calcium levels. The circadian variation in astrocytic calcium signaling, particularly in response to stimuli like ATP, can influence the release of neurotransmitters and modulate synaptic transmission. This can impact neuronal excitability, synaptic plasticity, and overall brain function.
Additionally, the circadian regulation of gap junction communication in astrocytes can affect the synchronization of neuronal activity across brain regions. Gap junctions allow for the direct exchange of ions and signaling molecules between astrocytes, enabling the coordination of neuronal networks. The day/night variations in gap junction communication can influence the spread of signals within the astrocytic syncytium, impacting the overall network activity and behavior.
In vivo, disruptions in the circadian regulation of astrocytic calcium signaling and gap junction communication could lead to altered neuronal function, impaired synaptic plasticity, and dysregulated brain activity. This could manifest as changes in behavior, cognition, and overall brain health, highlighting the importance of circadian rhythms in maintaining optimal neuronal function and behavior.

What other astrocyte-specific functions might be under circadian control, and how could disruption of these rhythms contribute to neurological disorders?

In addition to calcium signaling and gap junction communication, several other astrocyte-specific functions could be under circadian control. These may include the regulation of neurotransmitter uptake and release, energy metabolism, antioxidant defense mechanisms, and the clearance of neurotoxic substances. Disruption of the circadian rhythms in these processes could contribute to neurological disorders through various mechanisms.
For example, disturbances in the circadian regulation of neurotransmitter uptake and release by astrocytes could lead to imbalances in synaptic transmission, affecting neuronal communication and network activity. Altered energy metabolism rhythms in astrocytes may impact the availability of energy substrates for neurons, potentially leading to neuronal dysfunction and cognitive deficits. Disrupted antioxidant defense mechanisms could result in increased oxidative stress and neuroinflammation, contributing to neurodegenerative diseases.
Overall, the dysregulation of circadian rhythms in astrocyte-specific functions could disrupt the homeostasis of the brain microenvironment, impair neuronal function, and contribute to the pathogenesis of neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, and mood disorders.

Could targeting the circadian regulation of astrocyte calcium homeostasis and gap junctions provide novel therapeutic avenues for sleep disorders or other brain health issues?

Targeting the circadian regulation of astrocyte calcium homeostasis and gap junctions could indeed offer novel therapeutic avenues for sleep disorders and other brain health issues. By modulating the circadian rhythms of astrocytic calcium signaling and gap junction communication, it may be possible to restore normal neuronal function, improve sleep quality, and alleviate symptoms of various brain health conditions.
For sleep disorders, interventions that target the circadian regulation of astrocytic calcium signaling could help regulate the sleep-wake cycle, promote healthy sleep patterns, and enhance overall sleep quality. By synchronizing astrocytic functions with the body's internal clock, disruptions in sleep architecture and circadian rhythms could be mitigated.
In the context of other brain health issues, such as neurodegenerative diseases, mood disorders, and cognitive impairments, targeting the circadian regulation of astrocyte calcium homeostasis and gap junctions could help maintain neuronal health, reduce neuroinflammation, and support brain function. By restoring the balance of astrocytic functions through circadian interventions, it may be possible to slow down disease progression, improve cognitive function, and enhance overall brain health.
Overall, leveraging the circadian regulation of astrocyte calcium signaling and gap junction communication as therapeutic targets holds promise for addressing a wide range of brain health issues and promoting overall well-being.