Abstract
Postinhibitory rebound (PIR) is an intrinsic property often exhibited by neurons involved in generating rhythmic motor behaviors. Cell DE-3, a dorsal excitatory motor neuron in the medicinal leech exhibits PIR responses that persist for several seconds following the offset of hyperpolarizing stimuli and are suppressed in reduced Na+ solutions or by Ca2+ channel blockers. The long duration and Na+ dependence of PIR suggest a possible role for persistent Na+ current (I NaP). In vertebrate neurons, the neuroprotective agent riluzole can produce a selective block of I NaP. This study demonstrates that riluzole inhibits cell DE-3 PIR in a concentration- and Ca2+-dependent manner. In 1.8 mM Ca2+ solution, 50–100 µM riluzole selectively blocked the late phase of PIR, an effect similar to that of the neuromodulator serotonin. However, 200 µM riluzole blocked both the early and late phases of PIR. Increasing extracellular Ca2+ to 10 mM strengthened PIR, but high riluzole concentrations continued to suppress both phases of PIR. These results indicate that riluzole may suppress PIR via a nonspecific inhibition of Ca2+ conductances and suggest that a Ca2+-activated nonspecific current (I CAN), rather than I NaP, may underlie the Na+-dependent component of PIR.
Similar content being viewed by others
Abbreviations
- AHP:
-
Afterhyperpolarization
- DCC:
-
Discontinuous current clamp
- DE-3:
-
Dorsal excitatory motor neuron 3
- DMSO:
-
Dimethyl sulfoxide
- I CAN :
-
Ca2+-activated nonspecific current
- I h :
-
Hyperpolarization-activated cation current
- I NaP :
-
Persistent Na+ current
- V m :
-
Membrane potential
- NMDG:
-
N-methyl-d-glucamine
- PIR:
-
Postinhibitory rebound
- R input :
-
Input resistance
- RMP:
-
Resting membrane potential
- TEA:
-
Tetraethylammonium
- TTX:
-
Tetrodotoxin
References
Alvarado-Alvarez R, Arechiga H, Garcia U (2000) Serotonin activates a Ca2+-dependent K+ current in identified peptidergic neurons from the crayfish. J Exp Biol 203:715–723
Angstadt JD (2012) Serotonin and flufenamic acid modulate postinhibitory rebound responses of an excitatory motor neuron in the medicinal leech. Soc Neurosci Abstr 648:24
Angstadt JD, Friesen WOF (1993) Modulation of swimming behavior in the medicinal leech. I. Effects of serotonin on the electrical properties of swim-gating cell 204. J Comp Physiol A 172:223–234
Angstadt JD, Grassmann JL, Theriault KM, Levasseur SM (2005) Mechanisms of postinhibitory rebound and its modulation by serotonin in excitatory swim motor neurons of the medicinal leech. J Comp Physiol A 191:715–732
Angstadt JD, Simone AM, Peters NV (2011) Effects of riluzole on cell DE-3 of the medicinal leech: evidence that a persistent sodium-current contributes to postinhibitory rebound responses and bursting activity induced by calcium-channel blockers. Soc Neurosci Abstr 918:01
Arbas EA, Calabrese RL (1987) Ionic conductances underlying the activity of interneurons that control heartbeat in the medicinal leech. J Neurosci 7:3945–3952
Bellingham MC (2011) A review of the neural mechanisms of action and clinical efficiency of riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last decade? CNS Neurosci Ther 17:4–31
Bertrand S, Cazalets J (1998) Postinhibitory rebound during locomotor-like activity in neonatal rat motoneurons in vitro. J Neurophysiol 79:342–351
Burrell BD, Crisp KM (2008) Serotonergic modulation of afterhyperpolarization in a neuron that contributes to learning in the leech. J Neurophysiol 99:605–616
Cain SM, Snutch TP (2010) Contributions of T-type calcium channel isoforms to neuronal firing. Channels 4:475–482
Calabrese RL, Feldman JL (1997) Intrinsic membrane properties and synaptic mechanisms in motor rhythm generators. In: Stein PSG, Grillner S, Selverston AI, Stuart DG (eds) Neurons, networks and motor behavior. MIT, Cambridge, pp 119–130
Calvino MA, Iscla IR, Szczupak L (2005) Selective serotonin reuptake inhibitors induce spontaneous activity in the leech nervous system. J Neurophysiol 93:2644–2655
Cao YJ, Dreizler JC, Couey JJ, Houamed KM (2002) Modulation of recombinant and native neuronal SK channels by the neuroprotective drug riluzole. Eur J Pharm 449:47–54
Carr DB, Cooper DC, Ulrich SL, Spruston N, Surmeier DJ (2002) Serotonin receptor activation inhibits sodium current and dendritic excitability in prefrontal cortex via a protein kinase C-dependent mechanism. J Neurosci 22:6846–6855
Cepeda C, Chandler SH, Shumate LW, Levine MS (1995) Persistent Na+ conductance in medium-sized neostriatal neurons: characterization using infrared video microscopy and whole-cell patch clamp recordings. J Neurophysiol 74:1343–1348
Colmers WF, Lewis DV, Wilson WA (1982) Cs+ loading reveals Na+-dependent persistent inward current and negative slope resistance region in Aplysia giant neurons. J Neurophysiol 48:1191–1200
Crill W (1996) Persistent sodium current in mammalian central neurons. Ann Rev Physiol 58:349–362
Crisp KM, Mesce KA (2006) Beyond the central pattern generator: amine modulation of decision-making neural pathways descending from the brain of the medicinal leech. J Exp Biol 209:1746–1756
Crisp KM, Gallagher BR, Mesce KA (2012) Mechanisms contributing to the dopamine induction of crawl-like bursting in leech motoneurons. J Exp Biol 215:3028–3036
Davis RE, Stuart AE (1988) A persistent, TTX-sensitive sodium current in an invertebrate neuron with neurosecretory ultrastructure. J Neurosci 8:3978–3991
Del Negro CA, Koshiya N, Butera RJ, Smith JC (2002) Persistent sodium current, membrane properties and bursting behavior of pre-Bötzinger complex inspiratory neurons in vitro. J Neurophysiol 88:2242–2250
Duprat F, Lesage F, Patel AJ, Fink M, Romey G, Lazdunski M (2000) The neuroprotective agent riluzole activates the two P domain K+ channels TREK-1 and TRAAK. Mol Pharmacol 57:906–912
Elson RC, Selverston AI (1997) Evidence for a persistent Na+ conductance in neurons of the gastric mill rhythm generator of spiny lobsters. J Exp Biol 200:1795–1807
Fleidervish IA, Gutnick MJ (1996) Kinetics of slow inactivation of persistent sodium current in layer V neurons of mouse neocortical slices. J Neurophysiol 76:2125–2130
Franceschetti S, Guatteo E, Panzica F, Sancini G, Wanke E, Avanzini G (1995) Ionic mechanisms underlying burst firing in pyramidal neurons: intracellular study in rat sensorimotor cortex. Brain Res 696:127–139
French CR, Sah P, Buckett KJ, Gage PW (1990) A voltage-dependent persistent sodium current in mammalian hippocampal neurons. J Gen Physiol 95:1139–1157
Friesen WO (1985) Neuronal control of leech swimming movements: interactions between cell 60 and previously described oscillator neurons. J Comp Physiol 156:231–242
Friesen WO (1994) Reciprocal inhibition: a mechanism underlying oscillatory animal movements. Neurosci Behav Rev 18:547–553
Goaillard J, Taylor AL, Pulver SR, Marder E (2010) Slow and persistent postinhibitory rebound acts as an intrinsic short-term memory mechanism. J Neurosci 30:4687–4692
Gorelova NA, Yang CR (2000) Dopamine D1/D5 receptor activation modulates a persistent sodium current in rat prefrontal cortical neurons in vitro. J Neurophysiol 84:75–87
Grillner S, Ekeberg O, Manira AE, Lansner A, Parker D, Tegnér J, Wallén P (1998) Intrinsic function of a neuronal network—a vertebrate central pattern generator. Brain Res Rev 26:184–197
Guinamard R, Salle L, Simard C (2011) The non-selective monovalent cationic channels TRPM4 and TRPM5. Adv Exp Med Biol 704:147–171
Harris-Warrick RM (2002) Voltage-sensitive ion channels in rhythmic motor systems. Curr Opin Neurobiol 12:646–651
Harris-Warrick RM (2010) General principle of rhythmogenesis in central pattern networks. Prog Brain Res 187:213–222
Harvey PJ, Li X, Li Y, Bennett DJ (2006) 5-HT2 receptor activation facilitates a persistent sodium current and repetitive firing in spinal motoneurons of rats with and without chronic spinal cord injury. J Neurophysiol 96:1158–1170
Herbert T, Drapeau P, Pradier L, Dunn RJ (1994) Block of the rat IIA sodium channel α subunit by the neuroprotective drug riluzole. Mol Pharmacol 45:1055–1060
Hill AA, Lu J, Masino MA, Olsen OH, Calabrese RL (2001) A model of a segmental oscillator in the leech heartbeat neuronal network. J Comp Neurosci 10:281–302
Hille B (2001) Ion channels of excitable membranes, 3rd edn. Sinauer, Sunderland
Huang CS, Song JH, Nagata K, Yeh JZ, Narahashi T (1997) Effects of the neuroprotective agent riluzole on the high voltage-activated calcium channels of rat dorsal root ganglion neurons. J Pharm Exp Ther 282:1280–1290
Huguenard JR (1996) Low-threshold calcium currents in central nervous system neurons. Ann Rev Physiol 58:329–348
Johansen J, Kleinhaus AL (1988) Voltage clamp characterization of a calcium-dependent chloride conductance in a putative invertebrate motoneuron. J Comp Physiol A 162:57–65
Kim KJ, Cho HS, Choi SJ, Jeun SH, Kim SY, Sung KW (2008) Direct effects of riluzole on 5-hydroxytryptamine (5-HT)3 receptor – activated ion currents in NCB-20 neuroblastoma cells. J Pharmacol Sci 107:57–65
Kiss T (2003) Evidence for a persistent Na-conductance in identified command neurones of the snail, Helix pomatia. Brain Res 989:16–25
Kiss T (2008) Persistent Na-channels: origin and function. Acta Biologica Hung 59S:1–12
Kleinhaus AL, Angstadt JD (1995) Diversity and modulation of ionic conductances in leech neurons. J Neurobiol 27:419–433
Konoenko N, Shao L, Dudek FE (2004) Riluzole-sensitive slowly inactivating sodium current in rat suprachiasmatic nucleus neurons. J Neurophysiol 91:710–718
Kristan WB, Calabrese RL, Friesen WO (2005) Neuronal control of leech behavior. Prog Neurobiol 76:279–327
Lamanauskas N, Nistri A (2008) Riluzole blocks persistent Na+ and Ca2+ currents and modulates release of glutamate via presynaptic NMDA receptors on neonatal rat hypoglossal motoneurons in vitro. Eur J Neurosci 27:2501–2514
Lamas JA, Romero M, Reboreda A, Sanchez E, Ribeiro SJ (2009) A riluzole- and valproate-sensitive persistent sodium current contributes to the resting membrane potential and increases the excitability of sympathetic neurones. Eur J Physiol 458:589–599
Mangan PS, Curran GA, Hurney CA, Friesen WO (1994) Modulation of swimming behavior in the medicinal leech. III. Control of cellular properties in motor neurons by serotonin. J Comp Physiol A 175:709–722
Marder E, Bucher D (2001) Central pattern generators and the control of rhythmic movements. Curr Biol 11:R986–R996
McCormick DA (2004) Membrane potential and action potential. In: Byrne JH, Roberts JL (eds) From molecules to networks. An introduction of cellular and molecular neuroscience. Elsevier, New York, pp 115–140
Mittmann T, Alzheimer C (1998) Muscarinic inhibition of persistent Na+ current in rat neocortical pyramidal neurons. J Neurophysiol 79:1579–1582
Noh KM, Hwang JY, Shin HC, Koh JY (2000) A novel neuroprotective mechanism of riluzole: direct inhibition of protein kinase C. Neurobiol Dis 7:375–383
Olsen OH, Nadim F, Calabrese RL (1995) Modeling the leech heartbeat elemental oscillator. II. Exploring the parameter space. J Comput Neurosci 2:237–257
Opdyke CA, Calabrese RL (1994) A persistent sodium current contributes to oscillatory activity in heart interneurons of the medicinal leech. J Comp Physiol 175:781–789
Perez-Etchegoyen CB, Alvarez RJ, Rodriguez MJ, Szczupak L (2012) The activity of leech motoneurons during motor patterns is regulated by intrinsic properties and synaptic inputs. J Comp Physiol 198:239–251
Rela L, Yang SM, Szczupak L (2009) Calcium spikes in a leech nonspiking neuron. J Comp Physiol A 195:139–150
Sadreyev RI, Panchin YV (2000) The role of putative glutamatergic neurons and their connections in the locomotor central pattern generator of the mollusk, Clione limacina. Comp Biochem Physiol A 126:193–202
Sandler VM, Puil E, Schwarz DWF (1998) Intrinsic response properties of bursting neurons in the nucleus principalis trigemini of the gerbil. Neuroscience 83:891–904
Sangrey T, Jaeger D (2010) Analysis of distinct short and prolonged components in rebound spiking of deep cerebellar nucleus neurons. Eur J Neurosci 32:1646–1657
Simard JM, Tsymbalyuk O, Keledjian K, Ivanov A, Evanova S, Gerzanich V (2012) Comparative effects of glibenclamide and riluzole in a rate model of severe cervical spinal cord injury. Exp Neurol 233(566):574
Song JH, Huang CS, Nagata K, Yeh JZ, Narahashi T (1997) Differential action of riluzole on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels. J Pharmacol Exp Ther 282:707–714
Spadoni F, Hainsworth AH, Mercuri NB, Caputi L, Martella G, Lavaroni F, Bernardi G, Stefani A (2002) Lamotrigine derivatives and riluzole inhibit INa, P in cortical neurons. Neuroreport 13:1167–1170
Stefani A, Spadoni F, Bernardi G (1997) Differential inhibition by riluzole, lamotrigine, and phenytoin of sodium and calcium currents in cortical neurons: implications for neuroprotective strategies. Exp Neurol 147:115–122
Stuart AE (1970) Physiological and morphological properties of motoneurons in the central nervous system of the leech. J Physiol 209:627–646
Theiss RD, Kuo JJ, Heckman CJ (2007) Persistent inward currents in rat ventral horn neurons. J Physiol 580:507–522
Tohidi V, Nadim F (2009) Membrane resonance in bursting pacemaker neurons of an oscillatory network is correlated with network frequency. J Neurosci 29:6427–6435
Turrigiano G, LeMasson G, Marder E (1995) Selective regulation of current densities underlies spontaneous changes in the activity of cultured neurons. J Neurosci 15:3640–3652
Urbani A, Belluzi O (2000) Riluzole inhibits the persistent sodium current in mammalian CNS neurons. Eur J Neurosci 12:3567–3574
Walsh JP, Byrne JH (1989) Modulation of a steady-state Ca2+-activated, K+ current in tail sensory neurons of Aplysia: role of serotonin and cAMP. J Neurophysiol 61:32–44
Wu N, Enomoto A, Tanaka S, Hsiao C, Nykamp DQ, Izhikevich E, Chandler SH (2005) Persistent sodium currents in mesencephalic V neurons participate in burst generation and control of membrane excitability. J Neurophysiol 93:2710–2722
Acknowledgments
This work was made possible by generous support from Siena College, including a Summer Research Fellowship to JDA and a Summer Scholars Research Fellowship to AMS. All experiments are in accordance with current laws on animal experimentation and care in the USA.
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical standard
The authors declare that experiments were conducted in compliance with current laws of the United States of America.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
359_2014_919_MOESM1_ESM.eps
Supplementary Fig. 1 Block of PIR and suppression of evoked impulses in cells treated with 400 µM riluzole in a high Ca2+ background. Control and riluzole-treated cells were exposed to 10 mM Ca2+ solution throughout. a PIR in a representative control cell bathed in high Ca2+ solution with 0.4 % DMSO. b Block of PIR in a separate cell exposed to 400 µM riluzole and 0.4 % DMSO. c Action potentials evoked in a control cell (same cell as in a) during injection of +0.5 or +1 nA current pulses. d Decreased firing in a cell exposed to 400 µM riluzole (same cell as in b). This cell fired 13 spikes during the +0.5 nA pulse, a response consistent with a majority (5/7) of riluzole-treated cells, which fired between 10 and 16 spikes during the 1-s stimulus. The remaining two cells fired only a single spike at the onset of the depolarizing response. In cells firing multiple times, the action potentials appeared to terminate progressively sooner as current pulse amplitude was increased. No significant effect of 400 µM riluzole on the peak-to-trough amplitude of evoked spikes was detected. Note the shorter time scales in c and d. (EPS 234511 kb)
Rights and permissions
About this article
Cite this article
Angstadt, J.D., Simone, A.M. Riluzole suppresses postinhibitory rebound in an excitatory motor neuron of the medicinal leech. J Comp Physiol A 200, 759–775 (2014). https://doi.org/10.1007/s00359-014-0919-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00359-014-0919-x