title: Presynaptic Na+ channels: locus, development, and recovery from inactivation at a high-fidelity synapse.
abstract: Na+ channel recovery from inactivation limits the maximal rate of neuronal firing. However, the properties of presynaptic Na+ channels are not well established because of the small size of most CNS boutons. Here we study the Na+ currents of the rat calyx of Held terminal and compare them with those of postsynaptic cells. We find that presynaptic Na+ currents recover from inactivation with a fast, single-exponential time constant (24 degrees C, tau of 1.4-1.8 ms; 35 degrees C, tau of 0.5 ms), and their inactivation rate accelerates twofold during development, which may contribute to the shortening of the action potential as the terminal matures. In contrast, recordings from postsynaptic cells in brainstem slices, and acutely dissociated, reveal that their Na+ currents recover from inactivation with a double-exponential time course (tau(fast) of 1.2-1.6 ms; tau(slow) of 80-125 ms; 24 degrees C). Surprisingly, confocal immunofluorescence revealed that Na+ channels are mostly absent from the calyx terminal but are instead highly concentrated in an unusually long (approximately 20-40 microm) unmyelinated axonal heminode. Outside-out patch recordings confirmed this segregation. Expression of Na(v)1.6 alpha-subunit increased during development, whereas the Na(v)1.2alpha-subunit was not present. Serial EM reconstructions also revealed a long pre-calyx heminode, and biophysical modeling showed that exclusion of Na+ channels from the calyx terminal produces an action potential waveform with a shorter half-width. We propose that the high density and polarized locus of Na+ channels on a long heminode are critical design features that allow the mature calyx of Held terminal to fire reliably at frequencies near 1 kHz.
authors.affiliation: The Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239-3098, USA.
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Leão
authors.forename: Christopher
authors.initials: C
authors.lastname: Kushmerick
authors.forename: Raphael
authors.initials: R
authors.lastname: Pinaud
authors.forename: Robert
authors.initials: R
authors.lastname: Renden
authors.forename: Geng-Lin
authors.initials: GL
authors.lastname: Li
authors.forename: Holger
authors.initials: H
authors.lastname: Taschenberger
authors.forename: George
authors.initials: G
authors.lastname: Spirou
authors.forename: S Rock
authors.initials: SR
authors.lastname: Levinson
authors.forename: Henrique
authors.initials: H
authors.lastname: von Gersdorff
mesh_terms: D000200:Action Potentials / Q000502:physiology / Q000528:radiation effects; D000344:Afferent Pathways / Q000502:physiology / Q000528:radiation effects; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001933:Brain Stem / Q000166:cytology / Q000254:growth & development; D019256:Cadmium Chloride / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D005455:Fluorescent Antibody Technique / Q000379:methods; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D018613:Microscopy, Confocal / Q000379:methods; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008959:Models, Neurological; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D018408:Patch-Clamp Techniques / Q000379:methods; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000502:physiology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D019789:Tetraethylammonium / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D062557:NAV1.6 Voltage-Gated Sodium Channel; D026902:Potassium Channel Blockers; D021122:Protein Subunits; C507811:Scn8a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; D019789:Tetraethylammonium; D019256:Cadmium Chloride