A1 astrocytes contribute to murine depression-like behavior and cognitive dysfunction, which can be alleviated by IL-10 or fluorocitrate treatment

Abstract

Background Astrocytes are crucial regulators in the central nervous system. Abnormal activation of astrocytes contributes to some behavior deficits. However, mechanisms underlying the effects remain unclear. Here, we studied the activation of A1 astrocytes and their contribution to murine behavior deficits. Methods A1 astrocytes were induced by treatment with lipopolysaccharide (LPS) in vitro. The functional phenotype of astrocytes was determined by quantitative RT-PCR, ELISA, and immunohistochemistry. To assess the role of A1 astrocytes in vivo, mice were injected intraperitoneally with LPS. Then, murine behaviors were tested, and the hippocampus and cortex were analyzed by quantitative RT-PCR, ELISA, and immunohistochemistry. The function of IL-10 and fluorocitrate on A1 astrocyte activation was also examined. Results Our results show that astrocytes isolated from B6.129S6-Il10tm1Flv/J homozygotes (IL-10tm1/tm1) were prone to characteristics of A1 reactive astrocytes. Compared with their wild-type counterparts, IL-10tm1/tm1 astrocytes exhibited higher expression of glial fibrillary acidic protein (GFAP). Whether or not they were stimulated with LPS, IL-10tm1/tm1 astrocytes exhibited enhanced expression of A1-specific transcripts and proinflammatory factors IL-1β, IL-6, and TNFα. In addition, IL-10tm1/tm1 astrocytes demonstrated hyperphosphorylation of STAT3. Moreover, astrocytes from IL-10tm1/tm1 mice showed attenuated phagocytic ability and were neurotoxic. IL-10tm1/tm1 mice demonstrated increased immobility time in the forced swim test and defective learning and memory behavior in the Morris water maze test. Moreover, enhanced neuroinflammation was found in the hippocampus and cortex of IL-10tm1/tm1 mice, accompanying with more GFAP-positive astrocytes and severe neuron loss in the hippocampus. Pretreatment IL-10tm1/tm1 mice with IL-10 or fluorocitrate decreased the expression of proinflammatory factors and A1-specific transcripts in the hippocampus and cortex, and then alleviated LPS-induced depressive-like behavior. Conclusion These results demonstrate that astrocytes isolated from B6.129S6-Il10tm1Flv/J homozygotes are prone to A1 phenotype and contribute to the depression-like behavior and memory deficits. Inhibiting A1 astrocyte activation may be an attractive therapeutic strategy in some neurodegenerative diseases.

Memory Impairment Related to NLRP3 Inflammasome Activation and TRPC5 Decrease in Hippocampal Excitatory Synapses in Microglia Knockout IL-10 Mice

“…This result is similar to the results of other relevant studies, in which IL-10 tm1/tm1 male mice with a low expression of IL-10 exhibited defective learning and memory behaviors in the MWM test [7]. A recent study showed that IL-10 produced from microglial cells in non-learned helpless mice is necessary to maintain learning and memory [19].Intranasal administration of IL-10 increased dendritic spine density by 2.0-and 4.3-fold in the dentate gyrus of non-learned helpless and learned helpless mice [19].…”

“…Increased IL-10 levels played a role in the process of enriched environment alleviated LPS-induced spatial learning and memory impairment [6]. IL-10 is an important molecule in the modulation of learning and memory dysfunction, as shown by the IL-10 tm1/tm1 mice that exhibited behavioral de cits in the MWM test [7].…”

Microglial activation contributes to cognitive impairments in rotenone-induced mouse Parkinson’s disease model

“…Neurotoxic astroglial activation is also considered to contribute to neuronal damage and subsequent cognitive impairment in animal models of neurodegeneration [ 12 ]. Consistently, blocking microglia-mediated conversion of astroglia to a neurotoxic phenotype by IL-10 or fluorocitrate alleviated LPS-induced depressive-like behavior and cognitive dysfunction in mice [ 13 ]. These results suggest that neuroinflammation mediated by microglia may contribute to cognitive decline in neurodegenerative disease.…”

Melatonin Ameliorates Axonal Hypomyelination of Periventricular White Matter by Transforming A1 to A2 Astrocyte via JAK2/STAT3 Pathway in Neonatal Rats Induced by Lipopolysaccharide Injection

“…Recent studies have reported that A1 astrocytes may gain neurotoxic functions and attack neurons and mature differentiated oligodendrocytes [39][40][41] . A1 reactive astrocytes can exert harmful effects because they secrete in ammatory factors such as IL-1β, IL-6, IFN-γ, and TNF-α along with the classical complement cascade genes and some unknown toxic factors deleterious to oligodendrocyte precursor cell differentiation, resulting in learning and memory impairments 13,42 . By contrast, A2 astrocyte activation was induced by ischemia, and activated A2 astrocyte are described to produce an array of neurotrophic factors, which are, therefore, considered to be protective to neurons or oligodendrocytes 16 .…”