AAV-shRNA Ttyh1 was used for gene knockdown. (From
BrainVTA)
The viruses used in this article from BrainVTA are in the table below
|
Custom-Made AAV |
rAAV2/8-Efla-mCherry-U6-Loxp-CMV-EGFP-Loxp-shRNA Ttyh1 |
Wen-Juan Han, Sui-Bin Ma, Wen-Bin Wu, Fu-Dong Wang, Xiu-Li Cao, Dong-Hao Wang, Hai-Ning Wu, Rou-Gang Xie, Zhen-Zhen Li, Fei Wang, Sheng-Xi Wu, Min-Hua Zheng, Ceng Luo, Hua Han
Pub Date: 2020-12-23,
DOI: 10.1007/s12264-020-00617-0,
Email: [email protected]
Tweety-homolog 1 (Ttyh1) is expressed in neural tissue and has been implicated in the generation of several brain diseases. However, its functional significance in pain processing is not understood. By disrupting the gene encoding Ttyh1, we found a loss of Ttyh1 in nociceptors and their central terminals in Ttyh1-deficient mice, along with a reduction in nociceptor excitability and synaptic transmission at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) in the basal state. More importantly, the peripheral inflammation-evoked nociceptor hyperexcitability and spinal synaptic potentiation recorded in spinal-PAG projection neurons were compromised in Ttyh1-deficient mice. Analysis of the paired-pulse ratio and miniature excitatory postsynaptic currents indicated a role of presynaptic Ttyh1 from spinal nociceptor terminals in the regulation of neurotransmitter release. Interfering with Ttyh1 specifically in nociceptors produces a comparable pain relief. Thus, in this study we demonstrated that Ttyh1 is a critical determinant of acute nociception and pain sensitization caused by peripheral inflammation.
Figure 1. Fluorescence in situ hybridization of Ttyh1 (green) in DRG neurons and SDH neurons.
In this study, the authors explored the role of Ttyh1 in DRG and spinal cord of pain circuit by combining an inflammatory pain model and behavioral investigation, biochemical analyses, and electrophysiological recordings as well as genetic manipulations. The analyses revealed that Ttyh1 in nociceptors as a critical molecular determinant of pro-nociceptive transmission. Hence, targeting Ttyh1 in nociceptors may represent a novel therapeutic target for analgesia with minimal side-effects.
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