Do Astrocytes Control Synaptic Connections in Neural Networks Relevant to Psychiatric Disorders? – AstroSyCo

Major depressive disorder (MDD) is ranked by the World Health Organization (WHO) among the leading causes of global disability. Current therapies for MDD remain insufficient, with only about one-third of patients responding to first-line treatments, and most failing to achieve full remission. These limitations emphasize the urgent need for new therapeutic strategies based on a better understanding of the biological mechanisms underlying the disorder.

Previous studies have identified reduced expression of synaptic protein genes and a decrease in synapse number as neurobiological hallmarks in the brains of MDD patients—particularly in the prefrontal cortex (PFC), a brain region crucial for regulating stress responses. Similar effects have been observed in rodent models of chronic stress, where activation of the glucocorticoid receptor (GR) by the stress hormone corticosterone (CORT) was implicated. In these models, antidepressant treatment—including ketamine—has been shown to reverse synaptic deficits in the PFC, suggesting that restoration of structural and functional synaptic plasticity is a key mechanism of antidepressant efficacy.

However, the cellular and molecular mechanisms driving neural circuit remodeling under stress and depression remain poorly understood. Recent findings by the research team revealed that astrocyte-specific genes involved in synapse formation and elimination are downregulated in the PFC of both MDD patients and chronically stressed rodents. Strikingly, these changes were prevented when GR was selectively deleted in astrocytes, indicating that astrocytes may play a previously unrecognized role in stress-induced synaptic dysfunction.

The project aims to directly test the hypothesis that stress-induced downregulation of astrocyte-specific genes leads to synapse loss in MDD. To achieve this, researchers will conduct a systematic analysis of the effects of astrocyte-specific gene knockdown—targeting those involved in synapse formation or elimination—on PFC-dependent behaviors, such as social interactions.

Using viral vectors encoding shRNA constructs, the team will manipulate astrocyte gene expression and assess behavioral consequences in mice through automated behavioral profiling (Social Box), which monitors approximately 60 spontaneous behaviors. In parallel, astrocytes will be genetically perturbed in a cell-type-specific and inducible manner using an innovative in utero electroporation technique developed by the team.

This approach allows for high-resolution imaging of Thy1-GFP-labeled dendrites in contact with either genetically modified or wild-type astrocytes within the same animal. Subsequent longitudinal two-photon microscopy will track how astrocyte-specific gene silencing affects stress- or ketamine-induced dendritic spine turnover. For genes associated with both behavioral and structural changes, correlative light and electron microscopy (CLEM) will be used to examine astrocyte-synapse ultrastructure in detail.

By combining behavioral, molecular, and high-resolution imaging approaches, this project aims to deliver unprecedented insights into the role of astrocytes in adult neural circuit remodeling. The findings are expected to significantly advance understanding of the neurobiological mechanisms underlying psychiatric disorders and open pathways toward the development of innovative treatment strategies for depression and related conditions.