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A new study published in the Journal of Immunity looked whether there was a potential link between early life stress and the onset of mental disorders.

“Individuals who suffer childhood abuse/neglect are much more likely to develop mental diseases, including depression and schizophrenia,” study author Wok-Suk Chung told us. “Additionally, stress has been shown to elicit a decrease in the number of excitatory synaptic connections in the brain and impair their functions. However, the underlying mechanism by which early life stress induces synaptic and behavioral symptoms later in life have been unclear.”

In this study, researchers specifically focused on astrocytes, which are the most abundant glial cells in the brain. Previously, they discovered that astrocytes play a critical role in remodeling developmental neural circuits through MEGF10 and MERTK phagocytic receptors.

“Since we initiated our project with in vitro phagocytosis screening results, we were able to narrow down the candidates affecting astrocytic phagocytosis,” Chung told us. “Therefore, based on our screening results, we hypothesized that stress hormones (or stress conditions) would enhance astrocytic phagocytosis within the brain as well.”

Since appropriate synapse pruning during the critical postnatal period is a key regulator for brain development, researchers expected that stress-induced synapse phagocytosis would evoke severe defects in circuit maturation and animal behaviors.

Synapse numbers dramatically increase right before and after birth. During the adolescent period in human case, there is massive synapse elimination, removing excessive and unnecessary synapses to form precise neuronal circuits. In some cases of brain disorders, inappropriate synapse pruning during this period can lead to disease onset. The research team focused on the role of glial functions in the synapse elimination process during this critical period.

“Over the past decade, it has been suggested that microglia play a role in synapse pruning through the complement cascade and other pathways, both in healthy and diseased brains,” Chung told us. “In the healthy brain, astrocytes also phagocytose unnecessary synapses through the MEGF10 and MERTK phagocytic receptors. However, it has been unknown whether astrocytic phagocytosis is involved in the development of brain disorders, such as mental disorders. Therefore, we initiated this project to reveal the physiological impact of astrocytic phagocytosis on brain development and their roles in mental disorders.”

Initially, the researchers’ aim was to identify the factors driving astrocytes to eliminate synapses within an in vitro system. To address this question, they conducted a screening of over 2,000 clinically approved compounds using purified astrocytes and synaptosomes. By labeling synaptosomes with a pH-sensitive dye, they were able to visualize and quantify the engulfed synaptosomes by astrocytes. Through this screening process, they discovered that synthetic glucocorticoids significantly increased synaptosome engulfment by astrocytes.

“For our in vivo experiments, we employed a mouse model of early social deprivation (ESD) to mimic early-life stress in humans,” Chung told us. “After confirming that ESD led to an increase in astrocytic phagocytosis of excitatory synapses, we generated astrocyte-specific GR or MERTK knock-out mice to genetically validate our hypothesis. Using these knock-out animals, we conducted electrophysiological experiments and behavioral analyses, including open field tests, elevated plus maze (EPM) tests, 3-chamber social tests, tail suspension tests (TST), and forced swim tests (FST), to observe the long-term effects of early life stress.”

The next step involved investigating the relevance of the findings to humans. For this, the research team utilized human cortical organoids (hCOs), which have been shown to closely mimic the neonatal human brain. Through a combination of in vitro, in vivo, and brain organoid experiments, they demonstrated that astrocytes indeed play a role as mediators of the synapse elimination process under early-life stress, thereby exerting a lasting impact on our neural circuitry and behaviors.

“In addition to the main findings, we also encountered some unexpected outcomes during our research,” Chung told us. “Firstly, a surprising revelation was the lack of participation by microglia in stress-induced synapse elimination. Microglia, another type of glial cell renowned for its involvement in synapse pruning during development, did not exhibit discernible differences in lysosomal content and MERTK expression in response to ESD. Consequently, it appears that the primary responsibility for stress-induced abnormal phenotypes in the ESD model lies with astrocytes.”

The research team’s primary focus rested on synapse loss, particularly the reduction of excitatory post-synapses. Throughout the experiments, a paradoxical observation emerged: despite the loss of excitatory post-synapses by astrocytes, there was a notable increase in neuronal firing in specific cortical regions when ESD mice engaged with objects. However, this abnormal spike in neuronal activity did not manifest when these ESD mice interacted with fellow mice. In light of this, the researchers delved into the possibility of astrocytes targeting and eliminating excitatory post-synapses solely on a specific type of neurons – inhibitory neurons, responsible for dampening neuronal excitation across the brain.

“In an astonishing turn, we indeed verified that astrocytes exclusively eliminate excitatory post-synapses on inhibitory neurons, sparing those originating from excitatory neurons,” Chung told us. “This selective action disrupts the equilibrium between excitatory and inhibitory signals in cortical regions. We firmly believe that this study marks the first instance of demonstrating such targeted synapse elimination by astrocytes, thereby influencing the onset of diseases.”

Chung believes these findings will play a crucial role in understanding and treating stress-induced mental disorders and that manipulating the immune response of astrocytes could serve as a therapeutic target for a range of brain disorders in the future.