Abstract
Peripheral nerves, subject to continuous elongation and compression during everyday movement, contain neuron fibers vital for movement and sensation. At supraphysiological strains resulting from trauma, chronic conditions, aberrant limb positioning, or surgery, conduction blocks occur which may result in chronic or temporary loss of function. Previous in vitro stretch models, mainly focused on traumatic brain injury modelling, have demonstrated altered electrophysiological behavior during localized deformation applied by pipette suction. Our aim was to evaluate the changes in voltage‐activated ion channel function during uniaxial straining of neurons applied by whole‐cell deformation, more physiologically relevant model of peripheral nerve trauma. Here, we quantified experimentally the changes in inwards and outwards ion currents and action potential (AP) firing in dorsal root ganglion‐derived neurons subject to uniaxial strains, using a custom‐built device allowing simultaneous cell deformation and patch clamp recording. Peak inwards sodium currents and rectifying potassium current magnitudes were found to decrease in cells under stretch, channel reversal potentials were found to be left‐shifted, and half‐maximum activation potentials right‐shifted. The threshold for AP firing was increased in stretched cells, although neurons retained the ability to fire induced APs. Overall, these results point to ion channels being damaged directly and immediately by uniaxial strain, affecting cell electrophysiological activity, and can help develop prevention and treatment strategies for peripheral neuropathies caused by mechanical trauma.
Highlights
Supraphysiological stretch of 5%–20% in peripheral nerves as a result of trauma, aberrant limb positioning, or surgery, is known to cause conduction blocks (Rickett, Connell, Bastijanic, Hegde, & Shi, 2011), the mechanisms are not fully understood
Voltage‐gated potassium channels, required for repolarization during action potential (AP) firing, are known to respond to mechanical stimuli, and their gating has been associated with the cell membrane’s mechanical state (Morris et al, 2015; Schmidt & MacKinnon, 2008). These results point to a close relationship between the mechanical environment of the cell membrane and ion channel function, suggesting that macro‐ scopic membrane strains, such as those occurring in vivo during sup‐ raphysiological nerve elongation can cause alterations in ion channel activity leading to impaired nerve electrophysiology
The aim of this study was to investigate the effects of whole‐cell uniaxial strain on single cell electrophysiology in DRG‐derived sen‐ sory neurons by whole‐cell patch clamping, and to quantify changes in ion channel properties during straining
Summary
Supraphysiological stretch of 5%–20% in peripheral nerves as a result of trauma, aberrant limb positioning, or surgery, is known to cause conduction blocks (Rickett, Connell, Bastijanic, Hegde, & Shi, 2011), the mechanisms are not fully understood. The effect of stretch on ion channel populations has been princi‐ pally investigated using localized membrane suction as a method for cell membrane deformation (Beyder et al, 2010; Morris & Juranka, 2007; Morris, Prikryl, & Joós, 2015; Wang et al, 2009) This allows simultaneous deformation and ion current recording, it does not closely replicate strains occurring in nerves in vivo, where the whole cell is subject to deformation. Voltage‐gated potassium channels, required for repolarization during AP firing, are known to respond to mechanical stimuli, and their gating has been associated with the cell membrane’s mechanical state (Morris et al, 2015; Schmidt & MacKinnon, 2008) These results point to a close relationship between the mechanical environment of the cell membrane and ion channel function, suggesting that macro‐ scopic membrane strains, such as those occurring in vivo during sup‐ raphysiological nerve elongation can cause alterations in ion channel activity leading to impaired nerve electrophysiology. We achieved this by ap‐ plying strain macroscopically to the entire cell by stretching neurons adherent to a deformable substrate, and using whole‐cell patch clamping on deformed cells to evaluate the immediate changes in ion channel and AP activity
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