Neuroinflammation and major depressive disorder: astrocytes at the crossroads

Abstract

Major depressive disorder is a complex and multifactorial condition, increasingly linked to neuroinflammation and astrocytic dysfunction. Astrocytes, along with other glial cells, beyond their classic functions in maintaining brain homeostasis, play a crucial role in regulating neuroinflammation and neuroplasticity, key processes in the pathophysiology of depression. This mini-review explores the involvement of astrocytes in depression emphasizing their mediation in neuroinflammation processes, the impact of astrocytic dysfunction on neuroplasticity, and the effect of some antidepressants on astrocyte reactivity. Recent evidence suggests that targeting astrocyte-related signaling pathways, particularly the balance between different astrocytic phenotypes, could offer promising evidence for therapeutic strategies for affective disorders. Therefore, a deeper understanding of astrocyte biology may open the way to innovative treatments aimed at mitigating depressive symptoms by impacting both neuroinflammation and imbalances in neuroplasticity.

Keywords: antidepressants; astrocytes; major depressive disorder; neuroinflammation; neuroplasticity.

Figure 1

A1 and A2 astrocyte phenotypes in depression: the inflammatory environment, characterized by a chronic state of stress, increases cortisol levels and promotes reactive astrogliosis. At least two types of astrocytes are described: neurotoxic astrocytes (A1), which can induce neuronal death, and neurotrophic astrocytes (A2), which support neuronal survival and tissue repair. The pro-inflammatory A1 phenotype may contribute to synaptic plasticity alterations, reducing dendritogenesis and synaptic contact formation, which could explain behavioral changes in regions like the hippocampus. A2 astrocytes produce neurotrophic factors such as GDNF and BDNF, as well as anti-inflammatory molecules. Some antidepressants inhibit the production of pro-inflammatory cytokines and promote the release of neurotrophins, potentially regulating A1 astrocyte activity and encouraging the transition to the A2 phenotype. Figure was created using BioRender.com.

Figure 2

BDNF–TrkB signaling: the BDNF protein and its receptor TrkB participate in various signaling pathways, including phospholipase Cγ (PLCγ), phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) pathways. Both ERK1/2 and cAMP response element binding protein (CREB) can translocate to the nucleus, where they phosphorylate CREB, promoting the transcription of genes involve in neuronal survival, dendritic growth, and synaptic plasticity. Figure was created using BioRender.com.