Childhood neglect and/or abuse can trigger severe stress that leads to significant alterations in neural networks and functions during development. These changes can contribute to the onset of mental illnesses, such as depression and schizophrenia. However, the precise mechanism underlying this process and potential methods for its control have remained elusive.

Figure 1. Childhood Abuse.

Figure 1 shows Childhood Abuse. On August 1st, a team of researchers from KAIST, led by Professor Won-Suk Chung from the Department of Biological Sciences, made a revelation regarding the origin of mental disorders resulting from childhood abuse trauma. Published in the international journal Immunity, renowned in the realm of immunology, their study identifies excessive synapse removal facilitated by astrocytes as the root cause of mental illnesses arising from childhood neglect and abuse.

The research team uncovered a significant link between heightened removal of excitatory synapses by astrocytes in response to stress hormones and the emergence of mental disorders due to childhood trauma. Previous clinical data had indicated a correlation between elevated stress levels and various mental illnesses, but the exact mechanism had remained enigmatic. The findings of this study are expected to have far-reaching implications for the prevention and treatment of such disorders.

In their quest to decode the mechanism governing the phagocytic role of astrocytes – responsible for engulfing and eliminating external substances – the researchers screened an FDA-approved drug. Their investigation revealed that synthetic glucocorticoids, commonly known as stress hormones, excessively heightened astrocyte-mediated phagocytosis. While glucocorticoids serve crucial roles in maintaining essential processes like carbohydrate metabolism and anti-inflammation, they are also released in response to stressors, enabling the body to respond adaptively. Prolonged and excessive exposure to glucocorticoids due to chronic stress, however, can lead to a range of mental disorders, including depression, cognitive impairments, and anxiety.

To understand how childhood stress alters astrocyte functions, the team employed mouse models subjected to early social deprivation. They discovered that stress hormones bind to astrocyte glucocorticoid receptors (GRs), resulting in a significant increase in the expression of Mer tyrosine kinase (MERK). This protein plays a pivotal role in astrocyte phagocytosis. Surprisingly, astrocytes selectively targeted excitatory synapses of specific neurons within the cerebral cortex. This abnormal synaptic elimination led to the formation of atypical neural networks, potentially culminating in complex behavioral abnormalities like social deficiencies and depression in adulthood.

Remarkably, the research team observed that microglia, which also contribute significantly to cerebral immunity, did not partake in synapse removal in the mouse models subjected to early social deprivation. This underscores the specific role of astrocyte-mediated responses to childhood stress hormones.

In an effort to ascertain the applicability of their findings to humans, the researchers employed human-induced pluripotent stem cell-derived brain organoids. Their experiments demonstrated that stress hormones induce astrocyte glucocorticoid receptor activation and subsequent phagocyte activation in these brain organoids, leading to the excessive elimination of excitatory synapses. By establishing the parallel response of mice and humans to stress-induced synaptic regulation, the researchers concluded that their discovery holds relevance for understanding and addressing mental disorders in humans. Professor Won-Suk Chung remarked, "This research sheds light on the previously unknown mechanism by which childhood stress contributes to brain diseases. Excessive astrocyte phagocytosis emerges as a pivotal factor." He further noted, "In the future, controlling astrocyte immune responses could serve as a foundational target for comprehending and treating brain disorders."

This research, authored by co-first authors Youkyeong Byun (Ph.D. candidate) and Nam-Shik Kim (post-doctoral associate) from the KAIST Department of Biological Sciences, was published on July 31 in the journal Immunity, a sibling publication of Cell and an eminent player in the immunology arena. Support for this study was provided by a National Research Foundation of Korea grant, the Korea Health Industry Development Institute (KHIDI), and the Korea Dementia Research Center (KDRC).

Source: KAIST

Cite this article:

Hana M (2023), KAIST Researchers Uncover Underlying Factor of Mental Disorders Triggered by Childhood Abuse, AnaTechmaz, pp.490