Time-dependent and selective microglia-mediated removal of spinal synapses in neuropathic pain

Yousefpour, Noosha; Locke, Samantha; Deamond, Haley; Wang, Chengyang; Marques, Lucas; St-Louis, Manon; Ouellette, Johanne; Khoutorsky, Arkady; Ribeiro‐da‐Silva, Alfredo

doi:10.1016/j.celrep.2023.112010

Cited by 23 publications

(14 citation statements)

References 82 publications

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“…Therefore, it is possible that A-fibres are protected from engulfment once the critical period is closed. This is further supported by a recent study on microglial engulfment of synapses following adult peripheral nerve injury after which VGAT and VGLUT2 synapses were engulfed 20 days post injury, but not afferent VGLUT1 or VGLUT3 synapses (Yousefpour et al, 2023). This suggests that the type of synapses engulfed is conserved following different types of peripheral injury, but the extent and timing of engulfment can differ.…”

Section: Discussionsupporting

confidence: 69%

Microglial phagocytosis mediates long-term restructuring of spinal GABAergic circuits following early life injury

Moulding

Jin

et al. 2023

Preprint

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Peripheral injury during the early postnatal period alters the somatosensory system, leading to behavioural hyperalgesia upon re-injury in adulthood. Spinal microglia have been implicated as the cellular mediators of this phenomenon, but the mechanism is unclear. We hypothesised that neonatal injury (1) alters microglial phagocytosis of synapses in the dorsal horn leading to long-term structural changes in neurons, and/or (2) trains microglia, leading to a stronger microglial response after re-injury in adulthood. Using hindpaw surgical incision as a model we showed that microglial density and phagocytosis increased in the dorsal horn region innervated by the hindpaw. Dorsal horn microglia increased engulfment of synapses following injury, with a preference for those expressing the vesicular GABA transporter VGAT and primary afferent A-fibre terminals in neonates. This led to a long-term reduction of VGAT density in the dorsal horn and reduced microglial phagocytosis of VGLUT2 terminals. We also saw an increase in apoptosis following neonatal injury, which was not limited to the dorsal horn suggesting that larger circuit wide changes are happening. In adults, hindpaw incision increased microglial engulfment of predominantly VGAT synapses but did not alter the engulfment of A-fibres. This engulfment was not affected by prior neonatal injury, suggesting that microglial phagocytosis was not trained. These results highlight microglial phagocytosis in the dorsal horn as an important physiological response towards peripheral injury with potential long-term consequences and reveals differences in microglial responses between neonates and adults.

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Section: Discussionsupporting

confidence: 69%

Microglial phagocytosis mediates long-term restructuring of spinal GABAergic circuits following early life injury

Moulding

Jin

et al. 2023

Preprint

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“…3 Peripheral nerve injury induced phagocytic microglia in the SDH; microglia showed morphological changes, characterized by retraction and thickening of processes and enlargement of soma. 9 In this study, CCI-induced phagocytic microglia show the same morphology. Microglia produce neuromodulators, including cytokines, that rapidly modulate synaptic plasticity.…”

Section: Increased Expression Of Psd-95 In Sdh Affected Phagocytic Mi...supporting

confidence: 59%

“…Previous research has reported abnormal activation of microglia in the phagocytosis of neuronal synapses 9 . We used immunofluorescence to evaluate morphological changes in microglia‐mediated synaptic phagocytosis induced by CCI.…”

Section: Resultsmentioning

confidence: 99%

“…7 In addition, microglial activation increases neuronal synaptic phagocytosis, causing pathological symptoms such as depression, Alzheimer's disease (AD), 8 and so forth, contributing to the development and maintenance of neuropathic pain. 9 As one of the treatments for neuropathic pain, traditional Chinese medicine is considered as an alternative choice. 10 Stauntonia chinensis injection (SCI) is produced from Stauntonia chinensis DC, a plant of the wood family that is an evergreen herb, mostly grown in southern China, with the Chinese name "Ye Mu Gua."…”

Section: Introductionmentioning

confidence: 99%

“…Neuropathic pain is often accompanied by activation of spinal cord microglia and neuroinflammation and 3 substantial changes in the SDH, and normal integration, processing, and transmission of sensory information are disrupted, which considerably contributes to the development of neuropathic pain 7 . In addition, microglial activation increases neuronal synaptic phagocytosis, causing pathological symptoms such as depression, Alzheimer's disease (AD), 8 and so forth, contributing to the development and maintenance of neuropathic pain 9 …”

Section: Introductionmentioning

confidence: 99%

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Stauntonia chinensis injection relieves neuropathic pain by increasing the expression of PSD‐95 and reducing the proliferation of phagocytic microglia

Deng,

Zou,

Qian

et al. 2023

Ibrain

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Neuroinflammation induced by engulfment of synapses by phagocytic microglia plays a crucial role in neuropathic pain. Stauntonia chinensis is extracted from Stauntonia chinensis DC, which has been used as a traditional Chinese medicine to control trigeminal neuralgia or sciatica. However, the specific anti‐neuralgia mechanism of Stauntonia chinensis is unknown. In this study, the analgesic effect of Stauntonia chinensis injection (SCI) in mice with neuropathic pain and the possible mechanisms are explored. We find that a local injection of 0.1 mL Stauntonia chinensis for 14 days can considerably relieve mechanical hyperalgesia and thermal hyperalgesia in mice with sciatic chronic constriction injury (CCI). Immunofluorescence staining shows that SCI reduces neuroinflammation in the spinal cord of CCI mice. RNA sequencing reveals that the expression of postsynaptic density protein 95 (PSD‐95), a postsynaptic scaffold protein, is downregulated in the spinal cord of CCI mice, but upregulated after SCI administration. Immunofluorescence experiments also demonstrate that SCI administration reverses microglia proliferation and PSD‐95 downregulation in CCI mice. These data suggest that SCI relieves neuropathic pain by increasing the expression of PSD‐95 and reducing the proliferation of phagocytic microglia.

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Establishment of a Magnetically Controlled Scalable Nerve Injury Model

Yang,

Liu,

Cao

et al. 2024

Advanced Science

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Animal models of peripheral nerve injury (PNI) serve as the fundamental basis for the investigations of nerve injury, regeneration, and neuropathic pain. The injury properties of such models, including the intensity and duration, significantly influence the subsequent pathological changes, pain development, and therapeutic efficacy. However, precise control over the intensity and duration of nerve injury remains challenging within existing animal models, thereby impeding accurate and comparative assessments of relevant cases. Here, a new model that provides quantitative and off‐body controllable injury properties via a magnetically controlled clamp, is presented. The clamp can be implanted onto the rat sciatic nerve and exert varying degrees of compression under the control of an external magnetic field. It is demonstrated that this model can accurately simulate various degrees of pathology of human patients by adjusting the magnetic control and reveal specific pathological changes resulting from intensity heterogeneity that are challenging to detect previously. The controllability and quantifiability of this model may significantly reduce the uncertainty of central response and inter‐experimenter variability, facilitating precise investigations into nerve injury, regeneration, and pain mechanisms.

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Time-dependent and selective microglia-mediated removal of spinal synapses in neuropathic pain

Cited by 23 publications

References 82 publications

Microglial phagocytosis mediates long-term restructuring of spinal GABAergic circuits following early life injury

Microglial phagocytosis mediates long-term restructuring of spinal GABAergic circuits following early life injury

Stauntonia chinensis injection relieves neuropathic pain by increasing the expression of PSD‐95 and reducing the proliferation of phagocytic microglia

Establishment of a Magnetically Controlled Scalable Nerve Injury Model

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