Astrocytes and the Psychiatric Sequelae of COVID-19: What We Learned from the Pandemic.

COVID-19, initially regarded as specific lung disease, exhibits an extremely broad spectrum of symptoms. Extrapulmonary manifestations of the disease also include important neuropsychiatric symptoms with atypical characteristics. Are these disturbances linked to stress accompanying every systemic infection, or are due to specific neurobiological changes associated with COVID-19? Evidence accumulated so far indicates that the pathophysiology of COVID-19 is characterized by systemic inflammation, hypoxia resulting from respiratory failure, and neuroinflammation (either due to viral neurotropism or in response to cytokine storm), all affecting the brain. It is reasonable to hypothesize that all these events may initiate or worsen psychiatric and cognitive disorders. Damage to the brain triggers a specific type of reactive response mounted by neuroglia cells, in particular by astrocytes which are the homeostatic cell par excellence. Astrocytes undergo complex morphological, biochemical, and functional remodeling aimed at mobilizing the regenerative potential of the central nervous system. If the brain is not directly damaged, resolution of systemic pathology usually results in restoration of the physiological homeostatic status of neuroglial cells. The completeness and dynamics of this process in pathological conditions remain largely unknown. In a subset of patients, glial cells could fail to recover after infection thus promoting the onset and progression of COVID-19-related neuropsychiatric diseases. There is evidence from post-mortem examinations of the brains of COVID-19 patients of alterations in both astrocytes and microglia. In conclusion, COVID-19 activates a huge reactive response of glial cells, that physiologically act as the main controller of the inflammatory, protective and regenerative events. However, in some patients the restoration of glial physiological state does not occur, thus compromising glial function and ultimately resulting in homeostatic failure underlying a set of specific neuropsychiatric symptoms related to COVID-19.