Synaptic Dynamics of the Feed-forward Inhibitory Circuitry Gating Mechanical Allodynia in Mice.

Abstract

BACKGROUND:

The authors' previous studies have found that spinal protein kinase C γ expressing neurons are involved in the feed-forward inhibitory circuit gating mechanical allodynia in the superficial dorsal horn. The authors hypothesize that nerve injury enhances the excitability of spinal protein kinase C γ expressing interneurons due to disinhibition of the feed-forward inhibitory circuit, and enables Aβ primary inputs to activate spinal protein kinase C γ expressing interneurons.

METHODS:

Prkcg-P2A-tdTomato mice were constructed using the clustered regularly interspaced short palindromic repeats and clustered regularly interspaced short palindromic repeats-associated nuclease 9 technology, and were used to analyze the electrophysiologic properties of spinal protein kinase C γ expressing neurons in both normal conditions and pathologic conditions induced by chronic constriction injury of the sciatic nerve. Patch-clamp whole cell recordings were used to identify the nature of the dynamic synaptic drive to protein kinase C γ expressing neurons.

RESULTS:

Aβ fiber stimulation evoked a biphasic synaptic response in 42% (31 of 73) of protein kinase C γ expressing neurons. The inhibitory components of the biphasic synaptic response were blocked by both strychnine and bicuculline in 57% (16 of 28) of neurons. Toll-like receptor 5 immunoreactive fibers made close contact with protein kinase C γ expressing neurons. After nerve injury, the percentage of neurons double-labeled for c-fos and Prkcg-P2A-tdTomato in animals walking on a rotarod was significantly higher than that in the nerve injury animals (4.1% vs. 9.9%, 22 of 539 vs. 54 of 548,P < 0.001). Aβ fiber stimulation evoked burst action potentials in 25.8% (8 of 31) of protein kinase C γ expressing neurons in control animals, while the proportion increased to 51.1% (23 of 45) in nerve injury animals (P = 0.027).

CONCLUSIONS:

The Prkcg-P2A-tdTomato mice the authors constructed provide a useful tool for further analysis on how the spinal allodynia gate works. The current study indicated that nerve injury enhanced the excitability of spinal protein kinase C γ expressing interneurons due to disinhibition of the feed-forward inhibitory circuit, and enabled Aβ primary inputs to activate spinal protein kinase C γ expressing interneurons.

• Authors: Qun Wang, Xiao Zhang, Xiaolan He, Shibin Du, Zhenhua Jiang, Peng Liu, Lu Qi, Chen Liang, Nan Gu, Yan Lu
• Journal: Anesthesiology (Anesthesiology) Vol. 132 Issue 5 Pg. 1212-1228 (05 2020) ISSN: 1528-1175 [Electronic] United States
• PMID: 32101975 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Topics

• Animals
• Female
• Ganglia, Spinal (chemistry, physiology)
• Hyperalgesia (physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Nerve Net (chemistry, physiology)
• Neural Inhibition (physiology)
• Organ Culture Techniques
• Pregnancy
• Random Allocation
• Synapses (chemistry, physiology)