Dysfunction of Microglial STAT3 Alleviates Depressive Behavior via Neuron–Microglia Interactions

Kwon, Sun-Ho; Han, Jeong Kyu; Choi, Miran; Kwon, Yong Jin; Kim, Sung Joon; Yi, Eun Hee; Shin, Jae Cheon; Cho, Ik Hyun; Kim, Byung Hak; Kim, Sang Jeong; Ye, Sang Kyu

doi:10.1038/npp.2017.93

Cited by 51 publications

(40 citation statements)

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“…The identified alterations in NF-κB p65 signaling in PBMCs are consistent with previously reported changes in NF-κB expression in post-mortem brain samples of patients with SCZ [69][70][71] and MDD [72] and with reports that polymorphisms in the NFKB1 gene are risk factors for treatment-refractory SCZ [73] and suicide [74]. Concurrently, microglial cell-specific Stat3 −/− knockout mice have been reported to show alterations in depressive-like behavior in animal models of major depression [75]. NF-κB and Stat3 are also primary mediators of pro-inflammatory cytokine signaling (e.g., IL-1β, TNF-α, and IL-6) associated with negative symptomatology in both SCZ [63,76] and MDD [77,78].…”

Section: Discussionsupporting

confidence: 89%

Exploring the neuropsychiatric spectrum using high-content functional analysis of single-cell signaling networks

et al. 2018

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Neuropsychiatric disorders overlap in symptoms and share genetic risk factors, challenging their current classification into distinct diagnostic categories. Novel cross-disorder approaches are needed to improve our understanding of the heterogeneous nature of neuropsychiatric diseases and overcome existing bottlenecks in their diagnosis and treatment. Here we employ high-content multi-parameter phospho-specific flow cytometry, fluorescent cell barcoding and automated sample preparation to characterize ex vivo signaling network responses (n = 1764) measured at the single-cell level in B and T lymphocytes across patients diagnosed with four major neuropsychiatric disorders: autism spectrum condition (ASC), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ; n = 25 each), alongside matched healthy controls (n = 100). We identified 25 nodes (individual cell subtype-epitope-ligand combinations) significantly altered relative to the control group, with variable overlap between different neuropsychiatric diseases and heterogeneously expressed at the level of each individual patient. Reconstruction of the diagnostic categories from the altered nodes revealed an overlapping neuropsychiatric spectrum extending from MDD on one end, through BD and SCZ, to ASC on the other end. Network analysis showed that although the pathway structure of the epitopes was broadly preserved across the clinical groups, there were multiple discrete alterations in network connectivity, such as disconnections within the antigen/integrin receptor pathway and increased negative regulation within the Akt1 pathway in CD4 T cells from ASC and SCZ patients, in addition to increased correlation of Stat1 (pY701) and Stat5 (pY694) responses in B cells from BD and MDD patients. Our results support the "dimensional" approach to neuropsychiatric disease classification and suggest potential novel drug targets along the neuropsychiatric spectrum.

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Section: Discussionsupporting

confidence: 89%

Exploring the neuropsychiatric spectrum using high-content functional analysis of single-cell signaling networks

et al. 2018

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“…Mice carrying a Cre transgene under the control of the Pcp2 promoter (Pcp2-Cre +/+ ) were purchased from the Jackson Laboratory (#004146, Tg(Pcp2-cre)2Mpin, Bar Harbor, ME, USA). STAT3 floxed (STAT3 fl/fl ) mice were kindly gifted from Dr. S Akira (Osaka University, Japan) (Kwon et al, 2017, Kiyoshi Takeda, 1998. Mice with a STAT3 deletion in Purkinje cells were generated by crossing mice with the floxed STAT3 allele with mice expressing Cre under the control of the Pcp2 promoter.…”

Section: Experimental Model and Subject Detailsmentioning

confidence: 99%

“…The genetic backgrounds for both the Cre and floxed STAT lines were C57BL/6J. Genotyping was performed as previously described (Kwon et al, 2017). The primers were specific for exons 22 and 23 of STAT3.…”

Section: Experimental Model and Subject Detailsmentioning

confidence: 99%

“…Immunohistochemical staining was performed as previously described (Kwon et al, 2017). The immunostaining was performed with primary antibodies for Stat3 (#4904, Cell Signaling, MA, USA), phosphor-Stat3(Tyr705) (#9145, Cell Signaling, MA, USA), c-fos (9F6) (#2250, Cell Signaling, MA, USA), and visualized using biotinylated goat anti-rabbit IgG (1:200, Vector Laboratories, CA, USA).…”

Section: Immunohistochemistrymentioning

confidence: 99%

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Ablation of STAT3 in Purkinje Cells Reorganizes Cerebellar Synaptic Plasticity in Long-Term Fear Memory Network

Han

Kwon

Kim

et al. 2020

Preprint

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Emotional memory processing, such as fear memory, engages a large neuronal network of brain regions including the cerebellum. However, the molecular and cellular mechanisms of the cerebellar cortex modulating the fear memory network is largely unknown. Here, we illustrate a novel mechanism by which synaptic signaling in cerebellar Purkinje cells (PCs) via STAT3 regulates long-term fear memory. Firstly, we generated PC-specific STAT3 knockout (STAT3PKO) mice. Transcriptome analyses revealed that STAT3 deletion results in transcriptional changes that lead to an increase in the expression of glutamate receptors. The amplitude of AMPA receptor-mediated excitatory postsynaptic currents at parallel fiber to PC synapses was larger in STAT3PKO mice than in wild-type littermates. Conditioning at the parallel fiber induced long-term depression of parallel fiber-PC synapses in STAT3PKO mice while the same manipulation induced long-term potentiation in wild-type littermates. Interestingly, STAT3PKO mice showed an aberrantly enhanced long-term fear memory. Neuronal activity in fear-related regions increased in fear-conditioned STAT3PKO mice. Our data suggest that STAT3-dependent molecular regulation in PCs is indispensable for proper expression of fear memory processing.

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“…Sphingosine‐1‐phosphate (S1P) receptors downregulate pro‐inflammatory cytokines and enhance pro‐regenerative responses after intracerebral hemorrhage (Marfia et al, ; Noda, Takeuchi, Mizuno, & Suzumura, ). The S1P receptor ligand FTY720 has been recently shown to attenuate microglia‐mediated neuroinflammation after white matter ischemic injury and to promote oligodendrogenesis via the transcription factor signal transducer activator of transcription (STAT)3 (Qin et al, ) (Figure ), one of the STAT transcription factors that regulate cytokine (El Kasmi et al, ) and chemokine (Kwon et al, ) production. Of note, S1P is a known activator of mitochondrial function (Nema & Kumar, ), suggesting a possible contribution of enhanced respiratory function to microglia phenotypic switch.…”

Section: Receptor and Channels Promoting Anti‐inflammatory Microglia mentioning

confidence: 99%

How to reprogram microglia toward beneficial functions

Fumagalli

Lombardi

Gressèns

et al. 2018

Glia

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Microglia, brain cells of nonneural origin, orchestrate the inflammatory response to diverse insults, including hypoxia/ischemia or maternal/fetal infection in the perinatal brain. Experimental studies have demonstrated the capacity of microglia to recognize pathogens or damaged cells activating a cytotoxic response that can exacerbate brain damage. However, microglia display an enormous plasticity in their responses to injury and may also promote resolution stages of inflammation and tissue regeneration. Despite the critical role of microglia in brain pathologies, the cellular mechanisms that govern the diverse phenotypes of microglia are just beginning to be defined. Here we review emerging strategies to drive microglia toward beneficial functions, selectively reporting the studies which provide insights into molecular mechanisms underlying the phenotypic switch. A variety of approaches have been proposed which rely on microglia treatment with pharmacological agents, cytokines, lipid messengers, or microRNAs, as well on nutritional approaches or therapies with immunomodulatory cells. Analysis of the molecular mechanisms relevant for microglia reprogramming toward pro-regenerative functions points to a central role of energy metabolism in shaping microglial functions. Manipulation of metabolic pathways may thus provide new therapeutic opportunities to prevent the deleterious effects of inflammatory microglia and to control excessive inflammation in brain disorders.

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Dysfunction of Microglial STAT3 Alleviates Depressive Behavior via Neuron–Microglia Interactions

Cited by 51 publications

References 51 publications

Exploring the neuropsychiatric spectrum using high-content functional analysis of single-cell signaling networks

Exploring the neuropsychiatric spectrum using high-content functional analysis of single-cell signaling networks

Ablation of STAT3 in Purkinje Cells Reorganizes Cerebellar Synaptic Plasticity in Long-Term Fear Memory Network

How to reprogram microglia toward beneficial functions

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