Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling

Gunner, Georgia; Cheadle, Lucas; Johnson, Kasey M.; Ayata, Pinar; Badimon, Ana; Mondo, Erica; Nagy, Martina; Liu, Liwang; Bemiller, Shane M.; Kim, Ki Wook; Lira, Sérgio A.; Lamb, Bruce T.; Tapper, Andrew R.; Ransohoff, Richard M.; Greenberg, Michael E.; Schaefer, Anne; Schafer, Dorothy P.

doi:10.1038/s41593-019-0419-y

Cited by 240 publications

(248 citation statements)

References 66 publications

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“…n.s., no significant difference. FNK shedding (Hundhausen et al, 2003) and sensory lesioninduced microglial synapse elimination (Gunner et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Microglia Mediate HIV-1 gp120-Induced Synaptic Degeneration in Spinal Pain Neural Circuits

Liu

Bae

et al. 2019

J. Neurosci.

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HIV-1 infection of the nervous system causes various neurological diseases, and synaptic degeneration is likely a critical step in the neuropathogenesis. Our prior studies revealed a significant decrease of synaptic protein, specifically in the spinal dorsal horn of patients with HIV-1 in whom pain developed, suggesting a potential contribution of synaptic degeneration to the pathogenesis of HIV-associated pain. However, the mechanism by which HIV-1 causes the spinal synaptic degeneration is unclear. Here, we identified a critical role of microglia in the synaptic degeneration. In primary cortical cultures (day in vitro 14) and spinal cords of 3-to 5-month-old mice (both sexes), microglial ablation inhibited gp120-induced synapse decrease. Fractalkine (FKN), a microglia activation chemokine specifically expressed in neurons, was upregulated by gp120, and knockout of the FKN receptor CX3CR1, which is predominantly expressed in microglia, protected synapses from gp120-induced toxicity. These results indicate that the neuron-to-microglia intercellular FKN/ CX3CR1 signaling plays a role in gp120-induced synaptic degeneration. To elucidate the mechanism controlling this intercellular signaling, we tested the role of the Wnt/␤-catenin pathway in regulating FKN expression. Inhibition of Wnt/␤-catenin signaling blocked both gp120-induced FKN upregulation and synaptic degeneration, and gp120 stimulated Wnt/␤-catenin-regulated FKN expression via NMDA receptors (NMDARs). Furthermore, NMDAR antagonist APV, Wnt/␤-catenin signaling suppressor DKK1, or knockout of CX3CR1 alleviated gp120-induced mechanical allodynia in mice, suggesting a critical contribution of the Wnt/␤-catenin/FKN/CX3R1 pathway to gp120-induced pain. These findings collectively suggest that HIV-1 gp120 induces synaptic degeneration in the spinal pain neural circuit by activating microglia via Wnt3a/␤-catenin-regulated FKN expression in neurons.Synaptic degeneration develops in the spinal cord dorsal horn of HIV patients with chronic pain, but the patients without the pain disorder do not show this neuropathology, indicating a pathogenic contribution of the synaptic degeneration to the development of HIV-associated pain. However, the mechanism underlying the synaptic degeneration is unclear. We report here that HIV-1 gp120, a neurotoxic protein that is specifically associated with the manifestation of pain in HIV patients, induces synapse loss via microglia. Further studies elucidate that gp120 activates microglia by stimulating Wnt/␤-catenin-regulated fractalkine in neuron. The results demonstrate a critical role of microglia in the pathogenesis of HIV-associated synaptic degeneration in the spinal pain neural circuit.

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“…n.s., no significant difference. FNK shedding (Hundhausen et al, 2003) and sensory lesioninduced microglial synapse elimination (Gunner et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Microglia Mediate HIV-1 gp120-Induced Synaptic Degeneration in Spinal Pain Neural Circuits

Liu

Bae

et al. 2019

J. Neurosci.

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“…Microglia are efficient phagocytes of synaptic material and apoptotic cells, which are key processes in the developing brain [19][20][21][22][23] . Specifically, once neuronal circuits are established, microglia contribute to the refinement of synaptic connections by engulfing synaptic elements in early post-natal life, in a fractalkine-and complement cascade-dependent manner [24][25][26][27][28][29] . This refinement is important for behavioral adaptation to the environment 27,[30][31][32][33] .…”

Section: Introductionmentioning

confidence: 99%

Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the developing brain

Madore

Leyrolle²,

Morel

et al. 2019

Preprint

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Omega-3 fatty acids (n-3 polyunsaturated fatty acids; n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in epidemiological studies, but the mechanisms by which a n-3 PUFA dietary imbalance affects CNS development are poorly understood. Active microglial engulfment of synaptic elements is an important process for normal brain development and altered synapse refinement is a hallmark of several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development. Our results show that maternal dietary n-3 PUFA deficiency increases microglial phagocytosis of synaptic elements in the developing hippocampus, through the activation of 12/15-lipoxygenase (LOX)/12-HETE signaling, which alters neuronal morphology and affects cognition in the postnatal offspring. While women of child bearing age are at higher risk of dietary n-3 PUFA deficiency, these findings provide new insights into the mechanisms linking maternal nutrition to neurodevelopmental disorders.One Sentence Summary: Low maternal omega-3 fatty acids intake impairs microgliamediated synaptic refinement via 12-HETE pathway in the developing brain.

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“…Microglia respond to changes in neuronal activity through directed migration of their highly motile processes (Nimmerjahn, Kirchhoff, & Helmchen, ; Wake, Moorhouse, Jinno, Kohsaka, & Nabekura, ). This enables dynamic interaction with synaptic elements, guided for example by purinergic signaling, and the resulting crosstalk between neuron and microglia contributes to experience‐dependent plasticity and the remodeling of brain circuits (Gunner et al, ; Parkhurst et al, ; Rogers et al, ; Schecter et al, ; Sipe et al, ). A further source of controversy related to the role of NMDARs in microglia comes from studies demonstrating that unlike their now prototypic, rapid chemotactic response to released purines, the motility of microglia is not influenced by exogenously supplied glutamate, at least not acutely.…”

Section: Discussionmentioning

confidence: 99%

Microglial NMDA receptors drive pro‐inflammatory responses via PARP‐1/TRMP2 signaling

Raghunatha

Vosoughi

Kauppinen

et al. 2020

Glia

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Chronic neuroinflammation driven by microglia is a characteristic feature associated with numerous neurodegenerative diseases. While acute inflammation can assist with recovery and repair, prolonged microglial pro-inflammatory responses are known to exacerbate neurodegenerative processes. Yet, detrimental outcomes of extended microglial activation are counterbalanced by beneficial outcomes including phagocytosis and release of trophic factors promoting neuronal viability. Our past work has shown that the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) is a key signaling hub driving pro-inflammatory microglia responses, but the signaling pathway maintaining PARP-1 activation remains elusive. While best understood for its role in promoting DNA repair, our group has shown that PARP-1 activity can be stimulated via Ca 2+ influx-dependent ERK1/2-mediated phosphorylation. However, to date, the route of Ca 2+ entry responsible for stimulating PARP-1 has not been identified. A likely candidate is via Ca 2+ -permeable transient receptor potential melastatin 2 (TRPM2) channels activated downstream of PARP-1 in a cascade that involves ADP-ribose (ADPR) production by poly(ADP-ribose) glycohydrolase (PARG). Here we demonstrate that NMDA receptor (NMDAR) stimulation in primary cultured microglia induces their proliferation, morphological activation and release of pro-inflammatory mediators. These responses were contingent on the recruitment of PARP-1, PARG and Ca 2+ permeable TRPM2 channels. Furthermore, we show that Ca 2+ influx is necessary to activate PARP-1/TRPM2 signaling, in an ERK1/2-dependent, but DNA damage independent, manner. Our findings, showing that PARP-1/TRPM2 mediate the pro-inflammatory effects of NMDAR stimulation, provides a unifying mechanism linking elevated glutamate levels to chronic neuroinflammation.

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Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling

Cited by 240 publications

References 66 publications

Microglia Mediate HIV-1 gp120-Induced Synaptic Degeneration in Spinal Pain Neural Circuits

Microglia Mediate HIV-1 gp120-Induced Synaptic Degeneration in Spinal Pain Neural Circuits

Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the developing brain

Microglial NMDA receptors drive pro‐inflammatory responses via PARP‐1/TRMP2 signaling

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