Stimulationinduced ectopicity and propagation win

Authors: Mathieu Lachance André Longtin Catherine E Morris Na Yu Béla Joós

Publish Date: 2014/08/12

Volume: 37, Issue: 3, Pages: 523-531

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Abstract

Neural tissue injuries render voltagegated Na+ channels Nav leaky thereby altering excitability disrupting propagation and causing neuropathic pain related ectopic activity In both recombinant systems and native excitable membranes membrane damage causes the kineticallycoupled activation and inactivation processes of Nav channels to undergo hyperpolarizing shifts This damageintensity dependent change called coupled leftshift CLS yields a persistent or “subthreshold” Nav window conductance Nodes of Ranvier simulations involving various degrees of mild CLS showed that as the system’s channel/pump fluxes attempt to reestablish ion homeostasis the CLS elicits hyperexcitability subthreshold oscillations and neuropathic type action potential AP bursts CLSinduced intermittent propagation failure was studied in simulations of stimulated axons but pump contributions were ignored leaving open an important question does mildinjury small CLS values pumps functioning well render propagationcompetent but still quiescent axons vulnerable to further impairments as the system attempts to cope with its normal excitatory inputs We probe this incipient diffuse axonal injury scenario using a 10node myelinated axon model Fully restabilized nodes with mild damage can we show become ectopic signal generators “ectopic nodes” because incoming APs stress Na+/K+ gradients thereby altering spike thresholds Comparable changes could contribute to acquired sodium channelopathies as diverse as epileptic phenomena and to the neuropathic amplification of normally benign sensory inputs Input spike patterns we found propagate with good fidelity through an ectopically firing site only when their frequencies exceed the ectopic frequency This “propagation window” is a robust phenomenon occurring despite Gaussian noise large jitter and the presence of several consecutive ectopic nodesWhether it originates from trauma ischemia degenerative disease sepsis chemical insults or other causes neuronal injuries lead to assorted “acquired sodium channelopathies” eg Novak et al 2009 Bialer 2012 The resulting sick excitable cells manifest diverse abnormalities such as hypersensitivity Greer et al 2012 Kocsis and Devor 2000 Liu et al 2000a ectopicity propagation anomalies Kajander and Bennett 1992 Sheen and Chung 1993 Tal et al 1999 Chul et al 2000 Liu et al 2000b c 2002 Amir et al 2002 Ma and LaMotte 2007 Greer et al 2012 and neuropathic pain Coutaux et al 2005 Truini and Cruccu 2006 Fazen and Ringkamp 2007 Costigan et al 2009 Nickel et al 2012 Recently it has been emphasized Morris et al 2012 that a pathological feature of sick excitable cells with acquired sodium channelopathies is blebtype damage of the excitable Navbearing membranes Vicious cycles involving Navleak Wolf et al 2001 Na/K pump insufficiency and secondary Caexcitotoxicity Schafer et al 2009 are a known pathological syndrome and blebtype Dinic et al 2012 damage can be seen as part of that syndrome Morris et al 2012 providing a plausible mechanistic explanation for Navleak in sick excitable cells Wang et al 2009 Phillips et al 2009 Jiang and Gonen 2012Using recombinant Nav16 node of Ranvier Nav isoform Wang et al 2009 showed via Na+dye and voltage clamp experiments that cellular trauma directly elicits TTXsensitive Na+loading and that membrane aspiration which produces bleb damage progressively and irreversibly causes what now is termed NavCLS or “coupled leftshift” Boucher et al 2012 With bleb damage Nav channel activation and inactivation availability undergo irreversible shifts in the hyperpolarizing direction leftshift Given the tight kinetic coupling between fast activation and fast inactivation in Nav channels Conti et al 1984 Bean 2007 their damageinduced shifts will have the same magnitude LS Wang et al 2009 Note that CLS is the name of the phenomenon while LS is a variable representing the CLS value and is thus italicized Because the steadystate g NaV leftshifts this corresponds to a “Navleak” Thus for mild CLS which is what interests us here the steadystate g NaV in the healthy V rest range will increase putting ion homeostasis under stress with the pumps continually overworkedPrevious node of Ranvier modeling established that when pumps are included in the system mild CLS alone induces action potential AP bursting Boucher et al 2012 in conjunction with subthreshold oscillations STOs Yu et al 2012 Such ectopic activity is a feature of neuropathic pain and is also seen in epileptic discharge Bialer 2012 Volman et al 2012 With ion gradients held fixed a large CLS applied to a single node will trigger ectopic activity or block propagation Boucher et al 2012 In those computations LS was tested from zero to 30 mV as it increased the damaged node first became hypersensitive then spontaneously active ectopic at increasing frequencies until above a certain LS the adjacent healthy nodes were unable to follow Thereafter only a fraction of the APs was transmitted and plotted against LS this fraction showed a sequence of plateaus ie phaselockings interlaced with narrow ranges of aperiodic behavior When stimulated the damaged axon achieved faithful transmission for small CLS but showed phaselocked propagation pattern with failures at higher LS values Boucher et al 2012 These studies of saltatory conduction explored a wide range of LS values 0–30 mV for fixed Nernst potentials with constant current for stimulation Additionally modeling excitability in the context of white matter trauma Volman and Ng 2013 incorporated NavCLS and found alterations in AP amplitude and propagation speedHere we model mildly damaged axons mild NavCLS the situation for incipient diffuse axonal injury With Na/K pumps operational in all nodes Nernst potentials are dynamic during saltatory AP propagation We find that concentration changes too small to be of consequence in healthy neurons can have qualitatively important effects in damaged nodesAdditionally by applying periodic or variously timed APlike spike input stimuli we examine effects of NavCLS on AP propagation fidelity In the case of peripheral neuropathies these findings would apply to the early acute phase of injury and neuropathic pain before central and peripheral sensitization have time to occur What abnormalities in spike count and timing are to be expected What propagated patterns will result and can they explain the painful amplification of normally benign stimuli These are the additional research questions considered here

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