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

Abstract

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.

Microgliosis, astrogliosis and loss of aquaporin-4 polarity in frontal cortex of COVID-19 patients

“…It is not known whether AQP4 dysregulation lasts after acute SARS-CoV2 infection and more studies are needed to test long-term effects of COVID-19 on AQP4 polarization, cognitive abilities and mental health. Together with results of other studies on the role of astrocytes in COVID-19 and long-COVID (Huang & Fishell, 2022; Murta, Villarreal, & Ramos, 2020; Rosu et al, 2022; Steardo et al, 2022; Tremblay et al, 2020; Zorec & Verkhratsky, 2023), our results imply an important role for astrocytes in neuroinflammation as well as neurological and mental disorders due to SARS-CoV-2 infection.…”

“…In addition, astrocytes are affected by and are often causal of neurological diseases (Lee, Wheeler, & Quintana, 2022; Lohr, 2023; Patel, Tewari, Chaunsali, & Sontheimer, 2019). In COVID-19, reactive astrogliosis has been reported, including increased expression of glial fibrillary acidic protein (GFAP), and glial markers were found elevated in plasma and cerebrospinal fluid (Hanson et al, 2022; Huang & Fishell, 2022; Kanberg et al, 2020; Rosu et al, 2022; Spanos et al, 2022; Steardo, Steardo, & Scuderi, 2022; Tremblay et al, 2020). In the present study, we investigated the astrocyte markers GFAP, calcium-binding protein S100B and aquaporin-4 (AQP4) as well as microgliosis in frontal lobe of COVID-19 brains using immunohistochemical staining and compared the results with those from control brains.…”

Associations between COVID-19 and putative markers of neuroinflammation: A diffusion basis spectrum imaging study

“…Specifically, inflammation in the central nervous system may occur as early as several weeks after the onset of SARS-CoV-2 infection (30-32), and last up to two years after the infection with widespread influences in the brain in individuals suffering from long-COVID (33,34). In additional to acute production of proinflammatory microglia (i.e., the most dominant immune cells in the brain) and a chronic loss of microglia (73), COVID-19 has also been linked to damages in astrocytes and oligodendrocytes, which may gain a functional recovery 60-90 days after the infection onset and subsequently lead to reductions in neuroinflammation (68)(69)(70), but may also ultimately lead to neuronal cell death in the cerebral cortex (68,71). These findings suggest that COVID-19 related inflammatory processes may diverge depending on the assessment timing (74).…”

“…Current evidence indicates that inflammation in the central nervous system may occur as early as several weeks after the onset of SARS-CoV-2 infection (33)(34)(35), and last up to two years after the infection with widespread influences in the brain in individuals suffering from long-COVID (22,36). Alongside acute production of proinflammatory microglia (i.e., the most dominant immune cells in the brain) and a chronic loss of microglia (76), damages in astrocytes and oligodendrocytes were also observed in relation to COVID-19, which may undergo functional recovery 60-90 days after the infection onset, subsequently resulting in reductions of neuroinflammation (72)(73)(74). Alternatively, these glia cell damages may ultimately lead to neuronal cell death in the cerebral cortex (72,77).…”

SARS-CoV-2-Induced Amyloidgenesis: Not One, but Three Hypotheses for Cerebral COVID-19 Outcomes

“…Astrocytes, like endothelial cells, are directly affected by SARS-CoV-2 [19,[23][24][25], which may compromise their ability to remove Aβ, leading to CAA. Astrocytic involvement in COVID-19 can be confirmed by elevated serum levels of specific markers, GFAP, and S100 calcium-binding B protein (S100B).…”