Selective silencing of NaV1.7 decreases excitability and conduction in vagal sensory neurons

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Abstract

Non-technical summary

Sodium channels are obligatory for the conduction of action potentials along axons. There are several different sodium channel subtypes expressed in vagal sensory neurons, and it is difficult to pharmacologically block these subtypes selectively. We used virally delivered shRNA to selectively block the production of one of the sodium channel subtypes expressed in vagal sensory neurons, namely NaV1.7, and found that by selectively inhibiting the expression of this channel the conduction of action potentials was blocked in the majority of vagal sensory neurons. This study also shows that NaV1.7 is required for the elicitation of classical vagal reflexes such as cough.

There has been much information learned in recent years about voltage gated sodium channel (NaV) subtypes in somatosensory pain signalling, but much less is known about the role of specific sodium channel subtypes in the vagal sensory system. In this study, we developed a technique using adeno-associated viruses (AAVs) to directly introduce shRNA against NaV1.7 subtype gene into the vagal sensory ganglia of guinea pigs in vivo. NaV1.7 gene expression in nodose ganglia was effectively and selectively reduced without influencing the expression of other sodium channel subtype genes including NaV1.1, 1.2, 1.3 1.6, 1.8, or 1.9. Using a whole cell patch-clamp technique, this effect on NaV1.7 gene expression coincided with a reduction in tetrodotoxin-sensitive sodium current, a requirement for much larger depolarizing stimulus to initiate action potentials, and reduction in repetitive action potential discharge. Extracellular recordings in the isolated vagus nerve revealed that the conduction of action potentials in sensory A- and C-fibres in many neurons was effectively abolished after NaV1.7 shRNA introduction. Moreover, bilateral NaV1.7 shRNA injected animals survived for several months and the vagal reflex behaviour, exemplified by citric acid-induced coughing, was significantly suppressed. These data indicate that selectively silencing NaV1.7 ion channel expression leads to a substantial decrease in neural excitability and conduction block in vagal afferent nerves.

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