Regulation of motoneuron excitability by KCNQ/Kv7 modulators (Lombardo & Harrington 2016)

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Accession:217882
" ... Computer simulations confirmed that pharmacological enhancement of KCNQ/Kv7 channel (M current) activity decreases excitability and also suggested that the effects of inhibition of KCNQ/Kv7 channels on the excitability of spinal MNs do not depend on a direct effect in these neurons but likely on spinal cord synaptic partners. These results indicate that KCNQ/Kv7 channels have a fundamental role in the modulation of the excitability of spinal MNs acting both in these neurons and in their local presynaptic partners. ..."
Reference:
1 . Lombardo J, Harrington MA (2016) Non-reciprocal mechanisms of up- and down-regulation of spinal motoneuron excitability by modulators of KCNQ/Kv7 channels. J Neurophysiol :jn.00446.2016 [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type: Neuron or other electrically excitable cell;
Brain Region(s)/Organism: Spinal motoneuron;
Cell Type(s): Spinal cord motor neuron;
Channel(s): I Potassium; I K; I Na,t; I M;
Gap Junctions:
Receptor(s):
Gene(s):
Transmitter(s):
Simulation Environment: NEURON;
Model Concept(s): Axonal Action Potentials;
Implementer(s): Lombardo, Joseph [josslomb at gmail.com];
Search NeuronDB for information about:  Spinal cord motor neuron; I Na,t; I K; I M; I Potassium;
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LombardoHarrington2016
readme.html
Gfluctdv.mod *
ghchan.mod *
kca2.mod *
kdrRL.mod *
Km.mod *
kv1_gp.mod
L_Ca.mod *
mAHP.mod *
na3n.mod
na3rp.mod *
naps.mod *
napsi.mod *
buttons.png
ctrl.png
FR3cablepas.hoc
FRMot3dendNaHH.hoc
gKm0.png
GraphicsKmModulators.hoc
ModifiedFRMotoneuron.hoc
mosinit.hoc
retigabine.png
standard_0.hoc
Tools.ses
XE991.png
                            
COMMENT
km.mod
Potassium channel, Hodgkin-Huxley style kinetics
Based on I-M (muscarinic K channel)
Slow, noninactivating
Author: Zach Mainen, Salk Institute, 1995, zach@salk.edu
	
ENDCOMMENT

INDEPENDENT {t FROM 0 TO 1 WITH 1 (ms)}

NEURON {
	SUFFIX Km
	USEION k READ ek WRITE ik
	RANGE n, gk, gbar
	RANGE ninf, ntau
	GLOBAL Ra, Rb
	GLOBAL q10, temp, tadj, vmin, vmax
}

UNITS {
	(mA) = (milliamp)
	(mV) = (millivolt)
	(pS) = (picosiemens)
	(um) = (micron)
} 

PARAMETER {
	v 		(mV)
	dt		(ms)
	gbar = 10   	(pS/um2)	: 0.03 mho/cm2
	tha  = -30	(mV)		: v 1/2 for inf
	qa   = 9	(mV)		: inf slope		
	Ra   = 0.001	(/ms)		: max act rate  (slow)
	Rb   = 0.001	(/ms)		: max deact rate  (slow)
	celsius		(degC)
	temp = 23	(degC)		: original temp 	
	q10  = 2.3			: temperature sensitivity
	vmin = -120	(mV)
	vmax = 100	(mV)
} 


ASSIGNED {
	a		(/ms)
	b		(/ms)
	ik 		(mA/cm2)
	gk		(pS/um2)
	ek		(mV)
	ninf
	ntau (ms)	
	tadj
}
 

STATE { n }

INITIAL { 
	trates(v)
	n = ninf
}

BREAKPOINT {
        SOLVE states
	gk = tadj*gbar*n
	ik = (1e-4) * gk * (v - ek)
} 

LOCAL nexp

PROCEDURE states() {   : Computes state variable n 
        trates(v)      : at the current v and dt.
        n = n + nexp*(ninf-n)
        VERBATIM
        return 0;
        ENDVERBATIM
}

PROCEDURE trates(v) {  :Computes rate and other constants at current v.
                       :Call once from HOC to initialize inf at resting v.
        LOCAL tinc
        TABLE ninf, nexp
	DEPEND dt, celsius, temp, Ra, Rb, tha, qa
	
	FROM vmin TO vmax WITH 199

	rates(v): not consistently executed from here if usetable_hh == 1
        tadj = q10^((celsius - temp)/10)  :temperature adjastment
        tinc = -dt * tadj
        nexp = 1 - exp(tinc/ntau)
}


PROCEDURE rates(v) {  :Computes rate and other constants at current v.
                      :Call once from HOC to initialize inf at resting v.

        a = Ra * (v - tha) / (1 - exp(-(v - tha)/qa))
        b = -Rb * (v - tha) / (1 - exp((v - tha)/qa))
        ntau = 1/(a+b)
	ninf = a*ntau
}

Lombardo J, Harrington MA (2016) Non-reciprocal mechanisms of up- and down-regulation of spinal motoneuron excitability by modulators of KCNQ/Kv7 channels. J Neurophysiol :jn.00446.2016[PubMed]

References and models cited by this paper

References and models that cite this paper

Alaburda A, Perrier JF, Hounsgaard J (2002) An M-like outward current regulates the excitability of spinal motoneurones in the adult turtle. J Physiol 540:875-81 [PubMed]

Battefeld A, Tran BT, Gavrilis J, Cooper EC, Kole MH (2014) Heteromeric Kv7.2-7.3 channels differentially regulate action potential initiation and conduction in neocortical myelinated axons. J Neurosci 34:3719-32 [PubMed]

Bean BP (2007) The action potential in mammalian central neurons. Nat Rev Neurosci 8:451-65 [PubMed]

Beaumont E, Gardiner PF (2003) Endurance training alters the biophysical properties of hindlimb motoneurons in rats. Muscle Nerve 27:228-36 [PubMed]

Brown DA, Passmore GM (2009) Neural KCNQ (Kv7) channels. Br J Pharmacol 156:1185-95 [PubMed]

Brownstone RM, Jordan LM, Kriellaars DJ, Noga BR, Shefchyk SJ (1992) On the regulation of repetitive firing in lumbar motoneurones during fictive locomotion in the cat. Exp Brain Res 90:441-55 [PubMed]

Brownstone RM, Krawitz S, Jordan LM (2011) Reversal of the late phase of spike frequency adaptation in cat spinal motoneurons during fictive locomotion. J Neurophysiol 105:1045-50 [Journal] [PubMed]

Carp JS, Wolpaw JR (1994) Motoneuron plasticity underlying operantly conditioned decrease in primate H-reflex. J Neurophysiol 72:431-42 [PubMed]

Conradi S, Ronnevi LO (1977) Ultrastructure and synaptology of the initial axon segment of cat spinal motoneurons during early postnatal development. J Neurocytol 6:195-210 [PubMed]

Corbin-Leftwich A, Mossadeq SM, Ha J, Ruchala I, Le AH, Villalba-Galea CA (2016) Retigabine holds KV7 channels open and stabilizes the resting potential. J Gen Physiol 147:229-41 [Journal] [PubMed]

Cordero-Erausquin M, Changeux JP (2001) Tonic nicotinic modulation of serotoninergic transmission in the spinal cord. Proc Natl Acad Sci U S A 98:2803-7 [Journal] [PubMed]

Cormery B, Beaumont E, Csukly K, Gardiner P (2005) Hindlimb unweighting for 2 weeks alters physiological properties of rat hindlimb motoneurones. J Physiol 568:841-50 [Journal] [PubMed]

Cullheim S, Fleshman JW, Glenn LL, Burke RE (1987) Membrane area and dendritic structure in type-identified triceps surae alpha motoneurons. J Comp Neurol 255:68-81 [PubMed]

   [6 reconstructed morphologies on NeuroMorpho.Org]

Dai Y, Carlin KP, Li Z, McMahon DG, Brownstone RM, Jordan LM (2009) Electrophysiological and pharmacological properties of locomotor activity-related neurons in cfos-EGFP mice. J Neurophysiol 102:3365-83 [Journal] [PubMed]

Dai Y, Jones KE, Fedirchuk B, McCrea DA, Jordan LM (2002) A modelling study of locomotion-induced hyperpolarization of voltage threshold in cat lumbar motoneurones. J Physiol 544:521-36 [PubMed]

   Activity dependent changes in motoneurones (Dai Y et al 2002, Gardiner et al 2002) [Model]

Dai Y, Jordan LM, Fedirchuk B (2009) Modulation of transient and persistent inward currents by activation of protein kinase C in spinal ventral neurons of the neonatal rat. J Neurophysiol 101:112-28 [Journal] [PubMed]

Dedek K, Kunath B, Kananura C, Reuner U, Jentsch TJ, Steinlein OK (2001) Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel. Proc Natl Acad Sci U S A 98:12272-7 [PubMed]

Derjean D, Bertrand S, Le Masson G, Landry M, Morisset V, Nagy F (2003) Dynamic balance of metabotropic inputs causes dorsal horn neurons to switch functional states. Nat Neurosci 6:274-81 [PubMed]

Devaux JJ, Kleopa KA, Cooper EC, Scherer SS (2004) KCNQ2 is a nodal K+ channel. J Neurosci 24:1236-44 [PubMed]

Durand J, Filipchuk A, Pambo-Pambo A, Amendola J, Borisovna Kulagina I, Guéritaud JP (2015) Developing electrical properties of postnatal mouse lumbar motoneurons. Front Cell Neurosci 9:349 [Journal] [PubMed]

FATT P (1957) Sequence of events in synaptic activation of a motoneurone. J Neurophysiol 20:61-80 [PubMed]

Fedirchuk B, Dai Y (2004) Monoamines increase the excitability of spinal neurones in the neonatal rat by hyperpolarizing the threshold for action potential production. J Physiol 557:355-61 [Journal] [PubMed]

Fink AJ, Croce KR, Huang ZJ, Abbott LF, Jessell TM, Azim E (2014) Presynaptic inhibition of spinal sensory feedback ensures smooth movement. Nature 509:43-8 [PubMed]

Gao BX, Ziskind-Conhaim L (1998) Development of ionic currents underlying changes in action potential waveforms in rat spinal motoneurons. J Neurophysiol 80:3047-61 [Journal] [PubMed]

Gu N, Vervaeke K, Hu H, Storm JF (2005) Kv7-KCNQ-M and HCN-h, but not KCa2-SK channels, contribute to the somatic medium after-hyperpolarization and excitability control in CA1 hippocampal pyramidal cells. J Physiol 566:689-715 [PubMed]

Heckman CJ (1994) Computer simulations of the effects of different synaptic input systems on the steady-state input-output structure of the motoneuron pool. J Neurophysiol 71:1727-39 [PubMed]

Heckman CJ, Mottram C, Quinlan K, Theiss R, Schuster J (2009) Motoneuron excitability: the importance of neuromodulatory inputs. Clin Neurophysiol 120:2040-54 [Journal] [PubMed]

Henze DA, Buzsaki G (2001) Action potential threshold of hippocampal pyramidal cells in vivo is increased by recent spiking activity. Neuroscience 105:121-30 [PubMed]

Hochman S, McCrea DA (1994) Effects of chronic spinalization on ankle extensor motoneurons. II. Motoneuron electrical properties. J Neurophysiol 71:1468-79 [Journal] [PubMed]

Hönigsperger C, Marosi M, Murphy R, Storm JF (2015) Dorsoventral differences in Kv7/M-current and its impact on resonance, temporal summation and excitability in rat hippocampal pyramidal cells. J Physiol 593:1551-80 [Journal] [PubMed]

   [20 reconstructed morphologies on NeuroMorpho.Org]

Huang A, Noga BR, Carr PA, Fedirchuk B, Jordan LM (2000) Spinal cholinergic neurons activated during locomotion: localization and electrophysiological characterization. J Neurophysiol 83:3537-47 [PubMed]

Jordan LM, McVagh JR, Noga BR, Cabaj AM, Majczynski H, Slawinska U, Provencher J, Leblond H, (2014) Cholinergic mechanisms in spinal locomotion-potential target for rehabilitation approaches. Front Neural Circuits 8:132 [Journal] [PubMed]

Kole MH, Stuart GJ (2012) Signal processing in the axon initial segment. Neuron 73:235-47 [PubMed]

Krawitz S, Fedirchuk B, Dai Y, Jordan LM, McCrea DA (2001) State-dependent hyperpolarization of voltage threshold enhances motoneurone excitability during fictive locomotion in the cat. J Physiol 532:271-81 [PubMed]

Kuba H, Yamada R, Ishiguro G, Adachi R (2015) Redistribution of Kv1 and Kv7 enhances neuronal excitability during structural axon initial segment plasticity. Nat Commun 6:8815 [Journal] [PubMed]

Leroy F, Lamotte d'Incamps B, Zytnicki D (2015) Potassium currents dynamically set the recruitment and firing properties of F-type motoneurons in neonatal mice. J Neurophysiol 114:1963-73 [Journal] [PubMed]

Li Y, Brewer D, Burke RE, Ascoli GA (2005) Developmental changes in spinal motoneuron dendrites in neonatal mice. J Comp Neurol 483:304-17 [PubMed]

   [17 reconstructed morphologies on NeuroMorpho.Org]

MacDonell CW, Power KE, Chopek JW, Gardiner KR, Gardiner PF (2015) Extensor motoneurone properties are altered immediately before and during fictive locomotion in the adult decerebrate rat. J Physiol 593:2327-42 [Journal] [PubMed]

Martinello K, Huang Z, Lujan R, Tran B, Watanabe M, Cooper EC, Brown DA, Shah MM (2015) Cholinergic afferent stimulation induces axonal function plasticity in adult hippocampal granule cells. Neuron 85:346-63 [Journal] [PubMed]

Mateos-Aparicio P, Murphy R, Storm JF (2014) Complementary functions of SK and Kv7-M potassium channels in excitability control and synaptic integration in rat hippocampal dentate granule cells. J Physiol 592:669-93 [Journal] [PubMed]

   Dentate granule cell: mAHP & sAHP; SK & Kv7/M channels (Mateos-Aparicio et al., 2014) [Model]

Miles GB, Dai Y, Brownstone RM (2005) Mechanisms underlying the early phase of spike frequency adaptation in mouse spinal motoneurones. J Physiol 566:519-32 [PubMed]

Miles GB, Hartley R, Todd AJ, Brownstone RM (2007) Spinal cholinergic interneurons regulate the excitability of motoneurons during locomotion. Proc Natl Acad Sci U S A 104:2448-53 [Journal] [PubMed]

Power KE, McCrea DA, Fedirchuk B (2010) Intraspinally mediated state-dependent enhancement of motoneurone excitability during fictive scratch in the adult decerebrate cat. J Physiol 588:2839-57 [Journal] [PubMed]

Powers RK, Heckman CJ (2015) Contribution of intrinsic motoneuron properties to discharge hysteresis and its estimation based on paired motor unit recordings. A simulation study. J Neurophysiol 114:184-198 [Journal] [PubMed]

   Discharge hysteresis in motoneurons (Powers & Heckman 2015) [Model]

Powers RK, Sawczuk A, Musick JR, Binder MD (2004) Multiple mechanisms of spike-frequency adaptation in motoneurones. J Physiol Paris 93:101-14 [PubMed]

Rekling JC, Funk GD, Bayliss DA, Dong XW, Feldman JL (2000) Synaptic control of motoneuronal excitability. Physiol Rev 80:767-852 [PubMed]

Rivera-Arconada I, Lopez-Garcia JA (2005) Effects of M-current modulators on the excitability of immature rat spinal sensory and motor neurones. Eur J Neurosci 22:3091-8 [Journal] [PubMed]

Schwarz JR, Glassmeier G, Cooper EC, Kao TC, Nodera H, Tabuena D, Kaji R, Bostock H (2006) KCNQ channels mediate IKs, a slow K+ current regulating excitability in the rat node of Ranvier. J Physiol 573:17-34 [Journal] [PubMed]

Shah MM, Migliore M, Valencia I, Cooper EC, Brown DA (2008) Functional significance of axonal Kv7 channels in hippocampal pyramidal neurons. Proc Natl Acad Sci U S A 105(22):7869-7874 [Journal] [PubMed]

   CA1 pyramidal neuron: functional significance of axonal Kv7 channels (Shah et al. 2008) [Model]

Sherrington CS (1906) Integrative Action of the Nervous System

Soldovieri MV, Miceli F, Taglialatela M (2011) Driving with no brakes: molecular pathophysiology of Kv7 potassium channels. Physiology (Bethesda) 26:365-76 [Journal] [PubMed]

Szûcs P, Odeh F, Szokol K, Antal M (2003) Neurons with distinctive firing patterns, morphology and distribution in laminae V-VII of the neonatal rat lumbar spinal cord. Eur J Neurosci 17:537-44 [PubMed]

Tatulian L, Delmas P, Abogadie FC, Brown DA (2001) Activation of expressed KCNQ potassium currents and native neuronal M-type potassium currents by the anti-convulsant drug retigabine. J Neurosci 21:5535-45 [PubMed]

Vinay L, Brocard F, Pflieger JF, Simeoni-Alias J, Clarac F (2000) Perinatal development of lumbar motoneurons and their inputs in the rat. Brain Res Bull 53:635-47 [PubMed]

Wainger BJ, Kiskinis E, Mellin C, Wiskow O, Han SS, Sandoe J, Perez NP, Williams LA, Lee S, B (2014) Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep 7:1-11 [Journal] [PubMed]

Wang HS, McKinnon D (1995) Potassium currents in rat prevertebral and paravertebral sympathetic neurones: control of firing properties. J Physiol 485 ( Pt 2):319-35 [PubMed]

Wang HS, Pan Z, Shi W, Brown BS, Wymore RS, Cohen IS, Dixon JE, McKinnon D (1998) KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science 282:1890-3 [PubMed]

Wilson JM, Hartley R, Maxwell DJ, Todd AJ, Lieberam I, Kaltschmidt JA, Yoshida Y, Jessell TM, (2005) Conditional rhythmicity of ventral spinal interneurons defined by expression of the Hb9 homeodomain protein. J Neurosci 25:5710-9 [Journal] [PubMed]

Yue C, Yaari Y (2004) KCNQ-M channels control spike afterdepolarization and burst generation in hippocampal neurons. J Neurosci 24:4614-24 [PubMed]

Zaczek R, Chorvat RJ, Saye JA, Pierdomenico ME, Maciag CM, Logue AR, Fisher BN, Rominger DH, (1998) Two new potent neurotransmitter release enhancers, 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone and 10,10-bis(2-fluoro-4-pyridinylmethyl)-9(10H)-anthracenone: comparison to linopirdine. J Pharmacol Exp Ther 285:724-30 [PubMed]

Zagoraiou L, Akay T, Martin JF, Brownstone RM, Jessell TM, Miles GB (2009) A cluster of cholinergic premotor interneurons modulates mouse locomotor activity. Neuron 64:645-62 [Journal] [PubMed]

(61 refs)