Nature Communications: Scientists Identified a Calcium Ion Channel Linked to Brain Inflammation

Astrocytes often contribute to the onset of brain inflammation. However, the molecular mechanisms regulating astrocyte reactivity and its relationship with neuroinflammatory outcomes remain complex and poorly understood. A recent research report titled "Astrocyte Reactivity and Inflammation-Induced Depression-Like Behaviors are Regulated by Orai1 Calcium Channels," published in the international journal Nature Communications, sheds light on how calcium channels in the nervous system play a crucial role in promoting brain inflammation.

Astrocytes are a predominant subtype of glial cells in the body's nervous system, responsible for various essential functions in the brain, including synaptic neurotransmitter clearance, metabolic support for neurons, and control of the blood-brain barrier. Beyond these established functions, recent research has unveiled that astrocytes can induce neuroinflammation, leading to significant tissue damage and alterations in animal behavior. Despite the abundance and widespread neuroinflammatory nature of astrocytes, there is limited knowledge concerning the molecular checkpoints that control astrocyte-mediated brain inflammation.

In this study, researchers from Prakriya's laboratory found that the calcium channel Orai1 plays a pivotal role in controlling astrocyte reactivity and its ability to produce and release inflammatory mediators. This is because the activity of astrocytes is regulated by intracellular calcium signaling. To investigate this, researchers initially bred mice lacking the Orai1 gene, which has been demonstrated to control calcium signaling in various mammalian cells, including immune cells and microglia. Mice lacking the Orai1 gene in astrocytes were unable to efficiently produce and release inflammatory cytokines. Moreover, researchers discovered that the absence of Orai1 signaling led to reduced cellular metabolic capabilities associated with glycolysis and mitochondrial pathways.

Fig.1 Orai1 mediates SOCE in hippocampal astrocytes.¹

Researchers also observed that mice lacking Orai1 in astrocytes did not exhibit an increase in brain inflammation levels when exposed to pro-inflammatory stimuli. Through this, Orai1 was revealed to regulate multiple interconnected cellular processes driving brain inflammation. Importantly, Orai1 astrocyte knockout mice were protected against the depressive effects associated with inflammatory-related behaviors. As it is known, individuals experiencing strong peripheral inflammation due to interference or major surgery subsequently exhibit symptoms akin to depression. Therefore, researchers questioned the contributions of astrocyte activation and calcium signaling in astrocytes to this depressive-like syndrome, an area of study that remains novel as the role of astrocyte calcium signaling in controlling brain inflammation has yet to be elucidated.

These findings confirm the significant role of Orai1 in regulating brain inflammation, a common feature of many neurological disorders. Therefore, the results of this study may assist scientists in developing novel therapies aimed at mitigating neuroinflammation in the body. Michaela Novakovic added that when observing the depressive-like behaviors exhibited after inflammatory challenges, wild-type mice displayed clear depressive-like behaviors, characterized by a lack of pleasure and helpless behavior. However, when examining mice with astrocyte-specific Orai1 knockout, they appeared to be somewhat protected. The impact of astrocyte-specific Orai1 on the motivational behavioral responses of mice after inflammatory stimuli may be specific, as other cognitive functions of the astrocyte knockout mice remained unaffected.

In summary, this study's results suggest that Orai1 may serve as a central signaling hub in controlling astrocyte reactivity and astrocyte-mediated brain inflammation, which are common in many neurological disorders.

Reference

1. Novakovic, Michaela M et al. “Astrocyte reactivity and inflammation-induced depression-like behaviors are regulated by Orai1 calcium channels.” Nat Commun. 2023;14(1):5500. Distributed under Open Access License CC BY 4.0 without modification.