Microgliopathy in poststroke depression: exploring mechanisms and therapeutic strategies

Poststroke depression (PSD) is a prevalent emotional disorder following stroke and can emerge immediately or several months later. It represents the complex interaction between early brain injury-induced damage (immediate depression) and bodily and psychological stress related to neurofunctional deficits (delayed depression), potentially representing two distinct but consecutive pathological processes. Microglia, the brain's resident immune cells, undergo structural and functional changes during ischemic injury and social stress, triggering various pathophysiological processes. In ischemic brain injury, microglia contribute to blood‒brain barrier disruption and neuronal damage via excessive phagocytosis, synaptic pruning, and cytokine release. In the depression-only model, microglial dysfunction is characterized by stress-induced dyshomeostasis, pro-inflammatory responses, neuronal phagocytosis, and even microglial decline, some of which are linked to gut microbiota dysbiosis. Ischemic brain injury may induce persistent alterations in microglial homeostasis, potentially increasing vulnerability to subsequent stress exposure. This proposed microglial sensitization model provides a conceptual framework for understanding delayed PSD, although direct causal evidence remains insufficient. Thus, PSD aligns more with "microgliopathy" than with depression-only. This review provides an introductory overview of "microglial and depression-only," as it may partially align with the characteristics of delayed PSD. The review also highlights potential antidepressant strategies targeting microglia. We propose that multitarget, optimized combination therapies targeting microglial states via various pathological pathways may represent promising approaches to overcome the limitations of traditional PSD treatments. Nonetheless, current challenges include the complexity of PSD modeling and the lack of multiomics studies targeting microglial function, which hinders a precise understanding of microglial roles.