Structural and functional properties of spinal dorsal horn neurons after peripheral nerve injury change overtime via astrocyte activation

Kurabe, Miyuki; Sasaki, Mika; Furutani, Kenta; Furue, Hidemasa; Kamiya, Yuichi; Baba, Hiroshi

doi:10.1016/j.isci.2022.105555

Cited by 6 publications

(7 citation statements)

References 48 publications

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“…These electrophysiological results were consistent with the α 2 δ-1 localization in excitatory and inhibitory neurons of the spinal dorsal horn. Both presynaptic and postsynaptic mechanisms have been suggested to be involved in the attenuation of inhibitory neurotransmissions after nerve injury ( Moore et al, 2002 ; Kurabe et al, 2022 ), but further studies are needed to elucidate the underlying mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Voltage-gated calcium channel subunit α2δ-1 in spinal dorsal horn neurons contributes to aberrant excitatory synaptic transmission and mechanical hypersensitivity after peripheral nerve injury

Koga

Kobayashi²,

Tsuda³

et al. 2023

Front. Mol. Neurosci.

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Neuropathic pain, an intractable pain symptom that occurs after nerve damage, is caused by the aberrant excitability of spinal dorsal horn (SDH) neurons. Gabapentinoids, the most commonly used drugs for neuropathic pain, inhibit spinal calcium-mediated neurotransmitter release by binding to α2δ-1, a subunit of voltage-gated calcium channels, and alleviate neuropathic pain. However, the exact contribution of α2δ-1 expressed in SDH neurons to the altered synaptic transmission and mechanical hypersensitivity following nerve injury is not fully understood. In this study, we investigated which types of SDH neurons express α2δ-1 and how α2δ-1 in SDH neurons contributes to the mechanical hypersensitivity and altered spinal synaptic transmission after nerve injury. Using in situ hybridization technique, we found that Cacna2d1, mRNA coding α2δ-1, was mainly colocalized with Slc17a6, an excitatory neuronal marker, but not with Slc32a1, an inhibitory neuronal marker in the SDH. To investigate the role of α2δ-1 in SDH neurons, we used clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system and showed that SDH neuron-specific ablation of Cacna2d1 alleviated mechanical hypersensitivity following nerve injury. We further found that excitatory post-synaptic responses evoked by electrical stimulation applied to the SDH were significantly enhanced after nerve injury, and that these enhanced responses were significantly decreased by application of mirogabalin, a potent α2δ-1 inhibitor, and by SDH neuron-specific ablation of Cacna2d1. These results suggest that α2δ-1 expressed in SDH excitatory neurons facilitates spinal nociceptive synaptic transmission and contributes to the development of mechanical hypersensitivity after nerve injury.

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Section: Discussionmentioning

confidence: 99%

Voltage-gated calcium channel subunit α2δ-1 in spinal dorsal horn neurons contributes to aberrant excitatory synaptic transmission and mechanical hypersensitivity after peripheral nerve injury

Koga

Kobayashi²,

Tsuda³

et al. 2023

Front. Mol. Neurosci.

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“…Expression at homeostasis is broad but uneven, with astrocytes in the superficial dorsal horn expressing notably more GFAP than those in deeper lamina [ 9 , 46 ]. Sciatic nerve constriction, spinal nerve ligation, spinal cord injury, CIPN, trigeminal nerve injury, and experimental autoimmune encephalitis (a mouse model of multiple sclerosis) have all been shown to cause GFAP upregulation in the murine SC [ 16 , 57 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ]. GFAP also appeared to be more highly expressed in the spinal cord of a human patient with chronic regional pain syndrome (CRPS), and spinal cords from patients with HIV-induced neuropathic pain [ 83 , 84 ].…”

Section: Sgcs and Astrocytes In Neuropathic Painmentioning

confidence: 99%

“…Astrocyte activation can alter synapses in the CNS through both traditional and “gliogenic” long-term potentiation (LTP), causing central sensitization [ 97 , 98 ] ( Figure 4 ). Nerve injury may even cause astrocyte-dependent necroptosis of dorsal horn neurons [ 75 ]. Adequate synapse formation during development requires the adhesion molecule hevin (high endothelial venule protein, also called SPARCL1), a glycoprotein which is secreted by astrocytes and enables the interaction of neuraxin (NRX1α) and neuroligin (NL1), bridging pre- and post-synaptic neurons [ 99 ].…”

Section: Sgcs and Astrocytes In Neuropathic Painmentioning

confidence: 99%

The Similar and Distinct Roles of Satellite Glial Cells and Spinal Astrocytes in Neuropathic Pain

McGinnis

2023

Cells

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Preclinical studies have identified glial cells as pivotal players in the genesis and maintenance of neuropathic pain after nerve injury associated with diabetes, chemotherapy, major surgeries, and virus infections. Satellite glial cells (SGCs) in the dorsal root and trigeminal ganglia of the peripheral nervous system (PNS) and astrocytes in the central nervous system (CNS) express similar molecular markers and are protective under physiological conditions. They also serve similar functions in the genesis and maintenance of neuropathic pain, downregulating some of their homeostatic functions and driving pro-inflammatory neuro-glial interactions in the PNS and CNS, i.e., “gliopathy”. However, the role of SGCs in neuropathic pain is not simply as “peripheral astrocytes”. We delineate how these peripheral and central glia participate in neuropathic pain by producing different mediators, engaging different parts of neurons, and becoming active at different stages following nerve injury. Finally, we highlight the recent findings that SGCs are enriched with proteins related to fatty acid metabolism and signaling such as Apo-E, FABP7, and LPAR1. Targeting SGCs and astrocytes may lead to novel therapeutics for the treatment of neuropathic pain.

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“…Expression at homeostasis is broad but uneven, with astrocytes in the superficial dorsal horn expressing notably more GFAP than those in deeper lamina (9,46). Sciatic nerve constriction, spinal nerve ligation, spinal cord injury, CIPN, trigeminal nerve injury, and experimental autoimmune encephalitis (a mouse model of multiple sclerosis) have all been shown to cause GFAP 7pregulateon in the murine SC (16,56,74,75,76,77,78,79,80,81). GFAP also appeared to be more highly expressed in the spinal cord of a human patient with chronic regional pain syndrome (CRPS), and spinal cords from patients with HIV-induced neuropathic pain (82,83).…”

Section: Gfapmentioning

confidence: 99%

“…4). Nerve injury may even cause astrocyte-dependent necroptosis of dorsal horn neurons (74). Adequate synapse formation during development requires the adhesion molecule hevin (high endothelial venule protein, also called SPARCL1), a glycoprotein which is secreted by astrocytes and enables the interaction of neuraxin (NRX1α) and neuroligin (NL1), bridging pre and postsynaptic neurons (98).…”

Section: Reactive Gliosis: Beyond Gfapmentioning

confidence: 99%

The Similar and Distinct Roles of Satellite Glial Cells and Astrocytes in Neuropathic Pain

McGinnis¹,

Ji²

2023

Preprint

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Preclinical studies have identified glial cells as pivotal players in the genesis and maintenance of neuropathic pain after nerve injury associated with diabetes, chemotherapy, major surgeries, and virus infections. Satellite glial cells (SGCs) in the dorsal root and trigeminal ganglia of the peripheral nervous system (PNS) and astrocytes in the central nervous system (CNS) express similar molecular markers and are protective under physiological conditions. They also serve similar functions in the genesis and maintenance of neuropathic pain, downregulating some of their homeostatic functions and driving pro-inflammatory neuro-glial interactions in the PNS and CNS, i.e. “gliopathy”. However, the role of SGCs in neuropathic pain is not simply as “peripheral astrocytes”. We delineate how these peripheral and central glia participate in neuropathic pain by producing different mediators, engaging different parts of neurons, and becoming active at different stages following nerve injury. Finally, we highlight the recent findings that SGCs are enriched with proteins related to fatty acid metabolism and signaling such as Apo-E, FABP7, and LPAR1. Targeting SGCs and astrocytes may lead to novel therapeutics for the treatment of neuropathic pain.

show abstract

Structural and functional properties of spinal dorsal horn neurons after peripheral nerve injury change overtime via astrocyte activation

Cited by 6 publications

References 48 publications

Voltage-gated calcium channel subunit α2δ-1 in spinal dorsal horn neurons contributes to aberrant excitatory synaptic transmission and mechanical hypersensitivity after peripheral nerve injury

Voltage-gated calcium channel subunit α2δ-1 in spinal dorsal horn neurons contributes to aberrant excitatory synaptic transmission and mechanical hypersensitivity after peripheral nerve injury

The Similar and Distinct Roles of Satellite Glial Cells and Spinal Astrocytes in Neuropathic Pain

The Similar and Distinct Roles of Satellite Glial Cells and Astrocytes in Neuropathic Pain

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