Investigating the roles of astrocytic synapse elimination in evoking mental disorders

Abstract

Childhood neglect and abuse are strongly associated with the development of mental disorders, where abnormal neural circuits and synapse loss are observed. However, it is unknown how the circuit and synapse pathology are initiated by childhood stressful events. In this study, I identified the stress hormone as a strong inducer for astrocyte-mediated synapse phagocytosis. Through in vitro and in vivo experiments, I showed that the stress hormone significantly increases the astrocytic expression of Mertk, one of the TAM phagocytic receptors, through glucocorticoid receptor (GR)-mediated transcriptional activation. Increasing the levels of stress hormone in postnatal mice through Early Social Deprivation (ESD) resulted in specific activation of GR-MERTK pathway as well as lysosomal activities in astrocytes, but not in microglia. Moreover, the excitatory synaptic density in various bran regions including somatosensory and frontal cortex was significantly reduced in ESD mice along with the significant increase in the amount of astrocytic engulfment of excitatory synapses originated from GABAergic neurons, which resulted in excitatory and inhibitory balance. Remarkably, I found that the loss of excitatory synapses and behavior symptoms found in ESD mice were substantially prevented by ablating either GR or MERTK specifically from astrocytes. Thus, this work reveals that the stress hormone activates excessive excitatory synapse elimination by astrocytic GR-MERTK pathway during early postnatal development, and that this event is sufficient in evoking mental disorder-like behaviors in mice, suggesting astrocytic GR-MERTK pathway as a new therapeutic target for treating the stress-induced brain disorders.