Children experience extreme stress when separated from their parents, neglected, or abused during childhood.
These stressful events can significantly alter the brain's neural circuitry and functions in adulthood, leading to mental illnesses like schizophrenia and depression. However, there has been little research into the causes of childhood stress-related mental illnesses and how to control them.
A research team at the Korea Advanced Institute of Science and Technology (KAIST), led by Professor Chung Won-suk of the Department of Life Sciences, has broken the impasse by becoming the first worldwide to identify that excessive synapse removal in astrocytes causes mental illnesses caused by childhood stress, such as child abuse and neglect.
The research team concluded so after conducting a clinical drug screen approved by the U.S. Food and Drug Administration to identify new mechanisms that regulate the role of astrocytes in engulfing and removing phagocytosis.
The team found that synthetic glucocorticoids, also known as stress hormones, significantly and abnormally increase the phagocytosis of astrocytes.
Glucocorticoids are vital in life-sustaining functions, such as glucose metabolism and anti-inflammation. They are released by external stimuli, such as stress, to allow the body to respond. However, excessive and prolonged exposure to glucocorticoids due to chronic stress can lead to various psychiatric disorders such as depression, cognitive impairment, and anxiety.
To confirm its findings, the team used a mouse model of early social deprivation to understand astrocyte functional changes caused by childhood stress.
As a result, Professor Chung's team found that stress hormones bind to the glucocorticoid receptor on astrocytes and significantly increase the expression of a receptor called Mer Tyrosine Kinase (MERTK), which plays an essential role in astrocyte phagocytosis.
The increased MERTK allowed the astrocytes to selectively feed on and reduce the excitatory synapses of specific neurons in various cortical regions of the brain, leading to the formation of abnormal neural circuitry that later resulted in complex behavioral abnormalities, including social deficits and depression in adulthood.
The team also observed that microglia, which, along with astrocytes, play an essential role in brain immune function, did not participate in synapse elimination in the mouse model of childhood social deficit, confirming that only astrocytes regulate the brain's environment in response to stress hormones during childhood stressful situations.
The team used brain organoids derived from human pluripotent-induced stem cells to determine their response to stress hormones to see if they could replicate the results in humans.
The researchers also found that in human brain organoids, stress hormones activated glucocorticoid receptors and phagocytic receptors on astrocytes, and those astrocytes excessively eliminated excitatory synapses.
By showing that the mechanisms of synaptic regulation in mice and humans in response to stress are the same, Professor Chung believes the team's findings may have applications in treating human psychiatric disorders.
"Until now, the mechanisms of childhood stress and the development of brain diseases have not been well understood, but this study demonstrates for the first time that excessive astrocyte phagocytosis may play an important role in developing psychiatric diseases," Professor Chung said. "Regulating the immune function of astrocytes may be a fundamental target for understanding and treating various brain diseases in the future."
The international journal Immunity published the results of the study.