How brain cells meant to help may be making depression worse

Microglial cells, the resident immune cells of the central nervous system (CNS), regulate inflammatory responses by releasing pro-inflammatory cytokines — chemical signaling molecules. While the neuroinflammatory functions of microglial cells are well-documented, the exact role of astrocytes (a specialized type of glial cell) in neural growth and development has remained unclear until recently. To shine light on the role of astrocytes in neuroinflammation and in the pathophysiology of MDD, a team of researchers, led by Dr. Gaurav Singhal from the Department of Surgery, University of Wisconsin, USA, conducted an in-depth review of literature. Their findings will be published in Neuroprotection.

Explaining the motivation behind the present study, Dr. Singhal says, “MDD is one of the leading causes of disability worldwide and affects more than 280 million people across all age groups and regions. Moreover, the economic burden of MDD is substantial, with annual costs in the United States alone exceeding $326 billion. Gaining insights into the role of astrocytes in neuroinflammation can aid the development of therapeutic approaches to treat depression and other psychiatric disorders.”

The research team began by conducting a comprehensive literature search using widely used online repositories such as PubMed and Google Scholar. They evaluated 226 research papers relevant to astrocytes, neuroinflammation, and depression. To ensure the high quality of their study, they followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

In their analysis, the researchers found that astrocytes were key to maintaining the structural integrity of synaptic junctions between neurons. The release of neurotrophic factors such as brain-derived neurotrophic factor and fibroblast growth factor-2 by astrocytes were critical for the promotion of neurite growth and synapse formation. Besides stabilizing the tripartite synapse comprising of neuron-astrocyte-neuron, astrocytes further facilitated the effective communication between neurons via regulation of the ionic environment. Notably, changes in astrocyte morphology and function were associated with poor synaptic connectivity, contributing to the development of depressive symptoms.

Furthermore, they discovered a critical mechanism involving activated microglia and astrocytes that resulted in sustained neuroinflammation in MDD. The first step of the mechanism was the release of pro-inflammatory cytokines like tumor necrosis factor-α and interleukin-1 from activated microglia cells. These signals subsequently induced the secretion of additional inflammatory chemicals from astrocytes, thereby amplifying neuroinflammation.

Elaborating on the molecular crosstalk between microglia and astrocytes during MDD, Dr. Singhal explains, “Increased intracellular calcium levels within astrocytes can induce the release of adenosine triphosphate (ATP), which, in turn, triggers a delayed calcium response in microglial cells. Following multiple cycles of astrocyte-released ATP-based activation,  microglial cells eventually undergo apoptosis or programed cell death.”

Additionally, preclinical studies involving murine models showed that astrocytic lactate dehydrogenase A enzyme, responsible for lactate production, is important for maintaining neuronal excitability. A process known as histone lactylation — where lactate molecules are added to histone proteins in DNA — was found to alter gene expression, thereby contributing to astrocyte-driven neuroinflammation.

Taken together, this study highlights the molecular mechanisms underlying astrocytic dysfunction, wherein astrocytes switch from a neuroprotective role to one that promotes neuroinflammation by increasing the expression and secretion of inflammatory cytokines.