AAV- shRNA(BDNF) was used for nociceptor-specific knockdown of BDNF. AAV- NR1 was used was used for overexpression of NR1 in nociceptive DRG neurons. AAV-DIO-BDNF-pHluorin was used for the analysis of BDNF secretion in presynaptic terminals of nociceptors. AAV-DIO-hM3Dq was used for chemogenetics manipulation in DRG. AVV-GCaMP6s was used for Calcium imaging in presynaptic terminals of nociceptors. (From
BrainVTA)
The viruses used in this article from BrainVTA are in the table below
|
Custom-Made AAV |
PT-0415-rAAV2/8-u6-Loxp-cmv-EGFP-Loxp-shRNA(BDNF)
PT-0552-rAAV2/8-u6-Loxp-cmv-EGFP-Loxp-shRNA control
PT-0395rAAV2/8-EF 1a-DIO-BDNF-pHhuorin-WPRE-pA
PT-3833-rAAV2/8-CMV-DIO-shBDNF-EGFP-WPRE-pA
PT-0298-rAAV2/8-nEF 1a-DIO-NR1-3Flag-WPREs-pA |
|
Chemogenetics |
PT-0019-rAAV2/8-hSyn-DIO-hM3D(Gq)-mCherry-WPRE-pA |
|
Calcium sensors |
PT-0196-rAAV2/8-CAG-DIO-GCaMP6s-WPRE-pA
PT-0071-rAAV2/8-Ef1a-DIO-GCaMp6s-WPRE-pA |
|
Control |
PT-0115-rAAV2/8-hSyn-DIO-mCherry-WPRE-pA
PT-0315-rAAV2/8-nEF 1a-DIO-3Flag-WPREs-pA |
Rou-Gang Xie, Wen-Guang Chu, Da-Lu Liu, Xu Wang, Sui-Bin Ma, Fei Wang, Fu-Dong Wang, Zhen Lin, Wen-Bin Wu, Na Lu, Ying-Ying Liu, Wen-Juan Han, Hui Zhang, Zhan-Tao Bai, San-Jue Hu, Hui-Ren Tao, Thomas Kuner, Xu Zhang, Rohini Kuner, Sheng-Xi Wu, Ceng Luo
Pub Date: 2022-02-07,
DOI: 10.1038/s41467-022-28429-y,
Email: [email protected]
Postsynaptic NMDARs at spinal synapses are required for postsynaptic long-term potentiation and chronic pain. However, how presynaptic NMDARs (PreNMDARs) in spinal nociceptor terminals control presynaptic plasticity and pain hypersensitivity has remained unclear. Here we report that PreNMDARs in spinal nociceptor terminals modulate synaptic transmission in a nociceptive tone-dependent manner. PreNMDARs depresses presynaptic transmission in basal state, while paradoxically causing presynaptic potentiation upon injury. This state-dependent modulation is dependent on Ca2+ influx via PreNMDARs. Small conductance Ca2+-activated K+ (SK) channels are responsible for PreNMDARs-mediated synaptic depression. Rather, tissue inflammation induces PreNMDARs-PKG-I-dependent BDNF secretion from spinal nociceptor terminals, leading to SK channels downregulation, which in turn converts presynaptic depression to potentiation. Our findings shed light on the state-dependent characteristics of PreNMDARs in spinal nociceptor terminals on modulating nociceptive transmission and revealed a mechanism underlying state-dependent transition. Moreover, we identify PreNMDARs in spinal nociceptor terminals as key constituents of activity-dependent pain sensitization.
Figure 1. A schematic model proposing a nociceptive tone-dependent role of PreNMDARs expressed in spinal terminals of nociceptors in spinal presynaptic plasticity in different conditions.
Utilizing transgenic mice with specific deletion of functional NMDARs from presynaptic nociceptor terminals, the authors report here that PreNMDARs modulate spinal presynaptic plasticity in a nociceptive tone-dependent manner. The findings shed light on the state-dependent characteristics of PreNMDARs in spinal nociceptor terminals on modulating pain signals transmission from the periphery to the central nervous system and revealed a mechanism underlying this state-dependent switch.
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