Microglia Loss and Astrocyte Activation Cause Dynamic Changes in Hippocampal [18F]DPA-714 Uptake in Mouse Models of Depression

Abstract

Major depression is a serious and chronic mental illness. However, its etiology is poorly understood. Although glial cells have been increasingly implicated in the pathogenesis of depression, the specific role of microglia and astrocytes in stress-induced depression remains unclear. Translocator protein (TSPO) has long been considered a marker of neuroinflammation and microglial activation. However, this protein is also present on astrocytes. Thus, it is necessary to explore the relationships between TSPO, microglia, and astrocytes in the context of depression. In this study, C57BL/6J male mice were subjected to chronic unpredictable stress (CUS) for 5 weeks. Subsequently, sucrose preference and tail suspension tests (TSTs) were performed to assess anhedonia and despair in these mice. [18F]DPA-714 positron emission tomography (PET) was adopted to dynamically assess the changes in glial cells before and 2, 4, or 5 weeks after CUS exposure. The numbers of TSPO+ cells, ionized calcium-binding adaptor molecule (Iba)-1+ microglial cells, TSPO+/Iba-1+ cells, glial fibrillary acidic protein (GFAP)+ astrocytes, TSPO+/GFAP+ cells, and TUNEL-stained microglia were quantified using immunofluorescence staining. Real-time PCR was used to evaluate interleukin (IL)-1β, IL-4, and IL-18 expression in the hippocampus. We observed that hippocampal [18F]DPA-714 uptake significantly increased after 2 weeks of CUS. However, the signal significantly decreased after 5 weeks of CUS. CUS significantly reduced the number of Iba-1+, TSPO+, and TSPO+/Iba-1+ cells in the hippocampus, especially in the CA1 and dentate gyrus (DG) subregions. However, this intervention increased the number of GFAP+ astrocytes in the CA2/CA3 subregions of the hippocampus. In addition, microglial apoptosis in the early stage of CUS appeared to be involved in microglia loss. Further, the expression of pro-inflammatory cytokines (IL-1β and IL-18) was significantly decreased after CUS. In contrast, the expression of the anti-inflammatory cytokine IL-4 was significantly increased after 2 weeks of CUS. These results suggested that the CUS-induced dynamic changes in hippocampal [18F]DPA-714 uptake and several cytokines may be due to combined microglial and astrocyte action. These findings provide a theoretical reference for the future clinical applications of TSPO PET.

Acute and Chronic Ethanol Effects during Adolescence on Neuroimmune Responses: Consequences and Potential Pharmacologic Interventions

“…In similar studies on male mice, AIE caused an increase in cluster of differentiation molecule 68 (CD68), indicative of phagocytic activity in microglia in other brain regions, including the dorsal and medial raphe nuclei as well as the dorsal horn or increased Iba1 density in the prefrontal cortex, but the findings are not universal. One study, using a mouse AIE model, observed a loss of hippocampal microglia after AIE, but the animals had also experienced stressful behaviors, which may have been a confounding factor in the microglial expression [44,45]. Moreover, in the same study, re-exposure to ethanol resulted in a bifurcated response with evidence of microglial proliferation concurrent with apoptotic-positive microglia [44].…”

Altered Expression of Astrocytic ATP Channels and Ectonucleotidases in the Cerebral Cortex and Hippocampus of Chronic Social Defeat Stress-Susceptible BALB/c Mice

“…Based on the recent literature, however, the function and expression of connexin 43 in astrocytes increases and decreases in the early and prolonged phases of depression, respectively, and in a chronic unpredictable stress model, the former phase is up to 2 weeks and the latter one is 5 or more weeks. 13,17,37,38) Lu et al demonstrate that in medial prefrontal cortex (mPFC) under stressed conditions, astrocyte activation, which stimulates ATP release via ATP channels, depends on activation of glucocorticoid receptors, and its activity is increased and decreased in the early and chronic phases, respectively, of stress exposure. 13) Although cerebral cortex used in this study included mPFC and thus, their findings not being directly comparable to ours, we suggested that astrocytic expression of connexin 43 and P2X7 receptors in the cerebral cortex might be increased in an early phase of depression, implying the necessity of a disease phase-specific therapeutic approach for ATP channels expressed by cortical astrocytes.…”

Astrocyte metabolism and signaling pathways in the CNS

“…Changes to astrocytic functions in depression primarily revolve around the neuroimmune state, neuronal transmission, and synaptic plasticity. Astrocytes can become reactive when chronically exposed to stress, which can lead to impairment of their functionalities, including intracellular and extracellular ionic regulation, gap junction-based cellular communication, and neurotransmitter metabolism ( Guo et al, 2022 ; Miguel-Hidalgo, 2022 ). Many studies have indicated that astrocytes play a critical role in regulating various inflammatory signal transductors, such as gp130, transforming growth factor β receptor, interferon-γ receptor, and estrogen receptor α ( Colombo and Farina, 2016 ; Zheng et al, 2021 ).…”