Link Between Childhood Stress, Glucocorticoids, and Mental Health: A Novel Role for Astrocytic Phagocytosis

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Childhood abuse and emotional neglect have long been associated with an increased risk of developing mental health conditions later in life, including depression and schizophrenia.

While numerous factors contribute to this complex relationship, recent research has shed light on the role of abnormal synapse loss and neural circuit wiring in individuals with mental health disorders. The underlying mechanisms by which early-life stress induces synaptic and behavioral deficits, however, remain largely unexplored.

Astrocytes, the most abundant cells in the brain, have emerged as key players in the process of synaptic remodeling during development and under various disease conditions. Previous studies have shown that astrocytes express specific phagocytic receptors, including Megf10 and Mertk, which are crucial for recognizing and eliminating redundant synaptic connections.

These findings suggest that astrocytes actively contribute to reshaping neural circuits in response to neural activity during brain development.

Distinct Roles of Glia-Mediated Synapse Elimination

Recent advancements have demonstrated the distinct roles played by astrocytes and microglia in the elimination of excitatory and inhibitory synapses in the adult brain.

Astrocytes are found to constantly eliminate unnecessary excitatory synaptic connections in the adult hippocampus through the Megf10 receptor, thereby maintaining the homeostasis of circuit connectivity critical for cognitive functions.

On the other hand, microglia have the capacity to control the number of inhibitory synapses through MERTK-dependent phagocytosis, highlighting the specific mechanisms by which different glial cells participate in synapse elimination.

Glucocorticoids and Astrocytic Phagocytosis

In a groundbreaking discovery, researchers have found that glucocorticoids, stress hormones released in response to various stressors, enhance astrocytic phagocytosis.

The glucocorticoid receptor (GR) has been identified as a key player in this process, as blocking GR activation or deleting MERTK in cultured astrocytes effectively prevents glucocorticoid-induced phagocytosis. This exciting finding suggests that GR-induced MERTK transcriptional activation is responsible for the enhanced astrocytic phagocytic activity in response to stress hormones.

Early Social Deprivation Mouse Model

To further investigate the implications of childhood stress on astrocytic phagocytosis, researchers adapted an early social deprivation (ESD) mouse model. This model aimed to mimic childhood stress conditions and examine its effects on astrocytic activity in various cortical regions. Under ESD conditions, the expression of astrocytic GR and MERTK, as well as the number of LAMP2+ lysosomes in astrocytes, were significantly increased.

These changes indicated heightened astrocytic phagocytic activity in response to stress.

Effects of Childhood Stress on Synaptic Density and Excitatory-Inhibitory Balance

The researchers observed that astrocytes in ESD mice exhibited heightened engulfment of PSD95-positive synapses on GABAergic neurons, resulting in a decrease in excitatory synaptic density and an excitatory-inhibitory imbalance. Consequently, this synaptic imbalance led to abnormal neuronal network activities and behavioral phenotypes in ESD mice. Importantly, ablating MERTK or GR specifically from astrocytes substantially prevented these effects, indicating the critical role of the GR-MERTK signaling pathway in mediating stress-induced excitatory synapse elimination.

Implications for Therapeutic Targeting

The findings from this research present exciting possibilities for therapeutic interventions in mental health disorders induced by childhood stress. By identifying the GR-MERTK signaling pathway as a critical player in stress hormone-induced astrocytic phagocytosis, researchers now have a potential therapeutic target for modulating synapse elimination.

By developing treatments that modulate this pathway, it may be possible to mitigate the impact of childhood stress on neural circuitry and ultimately reduce the risk of developing mental health conditions in adulthood.

Conclusion

The intricate relationship between childhood stress, mental health conditions, and synaptic deficits is becoming clearer with recent research into astrocytic phagocytosis. The role of glucocorticoids in enhancing astrocytic phagocytosis and the downstream effects on excitatory synapse elimination have unveiled a novel aspect of the brain’s response to stress.

By understanding these mechanisms, researchers are now one step closer to developing targeted therapies that may alleviate the long-term consequences of childhood stress on mental health. Ultimately, this research opens up promising avenues for future investigations and potential breakthroughs in the field of neuroscience and mental health.


reference link :https://www.cell.com/immunity/pdf/S1074-7613(23)00318-7.pdf

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