A New Outlook on Mental Illnesses: Glial Involvement Beyond the Glue

Abstract

Mental illnesses have long been perceived as the exclusive consequence of abnormalities in neuronal functioning. Until recently, the role of glial cells in the pathophysiology of mental diseases has largely been overlooked. However recently, multiple lines of evidence suggest more diverse and significant functions of glia with behavior-altering effects. The newly ascribed roles of astrocytes, oligodendrocytes and microglia have led to their examination in brain pathology and mental illnesses. Indeed, abnormalities in glial function, structure and density have been observed in postmortem brain studies of subjects diagnosed with mental illnesses. In this review, we discuss the newly identified functions of glia and highlight the findings of glial abnormalities in psychiatric disorders. We discuss these preclinical and clinical findings implicating the involvement of glial cells in mental illnesses with the perspective that these cells may represent a new target for treatment.

The search for true numbers of neurons and glial cells in the human brain: A review of 150 years of cell counting

“…The earliest such reports originated in the 19 th century (Hammarberg, 1895;Ferrero, 1947;Friede, 1953;Hempel and Treff, 1959;Schlote, 1959). While the degree and localization of abnormalities differed considerably between studies (Ferrero, 1947;Rowland and Mettler, 1949;Hempel and Treff, 1959;Benes, 1993;Ong€ ur et al, 1998;Harrison, 1999;Vawter et al, 2000;Todtenkopf et al, 2005;Bernstein et al, 2015;Elsayed and Magistretti, 2015), changes in glial cell number, densities, or GNRs in discrete brain regions have been confirmed in more recent studies employing stereological or IF methods for diseases including autism spectrum disorders, mood disorder, depression, schizophrenia, and Alzheimer's disease (Rajkowska, 2000;Cotter et al, 2001;Hof et al, 2003;Vostrikov et al, 2007;Morgan et al, 2010;Karlsen and Pakkenberg, 2011;Andrade-Moraes et al, 2013;Verkhratsky et al, 2014).…”

Oligodendroglia-lineage cells in brain plasticity, homeostasis and psychiatric disorders

“…A large body of literature has now identified widespread glial deficits across various mental illnesses, ranging from mood and anxiety disorders to schizophrenia and bipolar disorder [76]. For example, volumetric reduction in brain regions critical to MDD is a persistent finding in early post-mortem studies.…”

“…(F) NG2-glia are required for median eminence-mediated leptin sensing and body weight control [75]. (G) NG2-glia mediate behavioral responses in stress and sensorimotor gating, possibly through secreted factors [70,76,99] (H) NG2-glia regulate microglia through the hepatocyte growth factor (HGF) for the maintenance of neuronal function and survival [74]. …”

Subfield-specific Effects of Chronic Mild Unpredictable Stress on Hippocampal Astrocytes

“…Although neuronal and spine atrophy has been thought to underlie the volume reduction (Duman and Duman, 2015;Qiao et al, 2016;Sheline, 2003;Sousa et al, 2000), increasing evidence supports the involvement of astrocytes in the volumetric loss (Cobb et al, 2016;Czéh et al, 2005;Naskar and Chattarji, 2019;Rajkowska and Stockmeier, 2013;Rajkowska et al, 1999) and the pathophysiology of depression (Elsayed and Magistretti, 2015;Marathe et al, 2018). Astrocytes are profoundly affected as a result of depression, resulting in significant atrophy (Cobb et al, 2016;Cotter et al, 2001;Miguel-Hidalgo et al, 2000Ongür et al, 1998;Rajkowska and Stockmeier, 2013;Rajkowska et al, 1999).…”