β-pompilidotoxin modulates spontaneous activity and persistent sodium currents in spinal networks.
The origin of rhythm generation in mammalian spinal cord networks is still poorly understood. In a previous study, we showed that spontaneous activity in spinal networks takes its origin in the properties of certain intrinsically spiking interneurons based on the persistent sodium current (INaP). We also showed that depolarization block caused by a fast inactivation of the transient sodium current (INaT) contributes to the generation of oscillatory activity in spinal cord cultures. Recently, a toxin called beta-pompilidotoxin (β-PMTX) that slows the inactivation process of tetrodotoxin (TTX)-sensitive sodium channels has been extracted from the solitary wasp venom. In the present study, we therefore investigated the effect of β-PMTX on rhythm generation and on sodium currents in spinal networks. Using intracellular recordings and multielectrode array (MEA) recordings in dissociated spinal cord cultures from embryonic (E14) rats, we found that β-PMTX reduces the number of population bursts and increases the background asynchronous activity. We then uncoupled the network by blocking all synaptic transmission (APV, CNQX, bicuculline and strychnine) and observed that β-PMTX increases both the intrinsic activity at individual channels and the number of intrinsically activated channels. At the cellular level, we found that β-PMTX has two effects: it switches 58% of the silent interneurons into spontaneously active interneurons and increases the firing rate of intrinsically spiking cells. Finally, we investigated the effect of β-PMTX on sodium currents. We found that this toxin not only affects the inactivation of INaT but also increases the peak amplitude of the persistent sodium current (INaP). Altogether, theses findings suggest that β-PMTX acting on INaP and INaT enhances intrinsic activity leading to a profound modulation of spontaneous rhythmic activity in spinal networks.
Department of Physiology, University of Bern, Buehlplatz 5, CH-3012 Bern, Switzerland. magloire@pyl.unibe.ch
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Magloire
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Czarnecki
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Anwander
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Streit
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D019476:Insect Proteins / Q000494:pharmacology*; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D009415:Nerve Net / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology*; D010507:Periodicity; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014862:Wasp Venoms / Q000494:pharmacology
D019476:Insect Proteins; D009498:Neurotoxins; D015222:Sodium Channels; D014862:Wasp Venoms; C115329:pompilidotoxin beta