A molecular characterization and clinical relevance of microglia-like cells derived from patients with panic disorder

Abstract

Few studies report the microglia involvement in the pathogenesis of panic disorder (PD), although the crucial role of microglia in other neuropsychiatric diseases is being emphasized. In addition, there is no report to characterize the phenotypic and functional levels of PD patient-derived microglia to find their clinical relevance. Herein, we used a model to induce patient-derived microglia-like cells (iMGs) to clarify the molecular characteristics and function of PD-iMGs. We established iMGs from 17 PD patients and 16 healthy controls (non-psychiatric controls, HC). PD-iMGs showed increased T-cell death-associated gene-8 expression per the proposal of a previous in vivo study. In addition, we found that patient-derived iMGs showed reduced phagocytosis and increased TREM2 expression. We analyzed the phenotype of the PD-iMGs by RNA sequencing. The PD-iMGs clustered together distinct from HC-iMGs. Gene set enrichment analysis revealed the involvement of cholesterol biosynthesis and steroid metabolism in PD-iMGs. Regarding the cholesterol synthesis pathway, we discovered ACAT2 and DHCR7 as the most impacted genes related to a character of PD-iMGs compared to HC-iMGs. The ACAT2, a major cholesterol esterifier, was increased in PD-iMGs. Nevertheless, PD-iMGs did not show lipid droplet accumulation. Interestingly, ACAT2 expression was inversely correlated with the severity of depression and anxiety sensitivity to publicly observable anxiety reactions. We propose that microglia of PD patients have unique characteristics with dysregulation of cholesterol biosynthesis pathway and impaired phagocytosis, reflecting clinical phenotype.

Evaluation of the association of physical activity levels with self-perceived health, depression, and anxiety in Spanish individuals with high cholesterol levels: a retrospective cross-sectional study

“…In addition, in people without psychiatric pathology, an association has been found between elevated cholesterol levels and symptoms of anxiety or mild depressive states ( Rafter, 2001 ; Cheon, 2023 ). In the same way, high cholesterol levels have also been reported in female patients with panic disorders ( Bajwa et al, 1992 ; You et al, 2023 ). In contrast, some studies suggest that naturally low concentrations of lipids and lipoproteins are associated with depression as well as poor psychological health ( Rafter, 2001 ; Suarez, 1999 ).…”

Possible involvement of microglial P2RY12 and peripheral IL-10 in postpartum depression

“…Recent research suggests that microglia may also play a role in the development of MDD (Rajkowska and Miguel-Hidalgo, 2007 ; Felger and Lotrich, 2013 ; Najjar et al, 2013 ). Most animal studies have shown that microglia have a reactive form in response to chronic stress, leading to neuroinflammation in the brain (Sugama et al, 2007 ; Tynan et al, 2010 ) although there are controversial results (Han et al, 2015 ) because microglia can also induce or resolve inflammation, maintain synaptic plasticity, and show phagocytosis in healthy and diseased brains, depending on the microenvironment (Colonna and Butovsky, 2017 ; You et al, 2023 ). Additionally, treatments that target microglia, such as anti-inflammatory drugs, can improve depressive- and anxiety-like symptoms in animal models (Bay-Richter and Wegener, 2022 ) although clinical trials have failed (Miller and Pariante, 2020 ).…”