Na(v)1.6a is required for normal activation of motor circuits normally excited by tactile stimulation.
A screen for zebrafish motor mutants identified two noncomplementing alleles of a recessive mutation that were named non-active (nav(mi89) and nav(mi130)). nav embryos displayed diminished spontaneous and touch-evoked escape behaviors during the first 3 days of development. Genetic mapping identified the gene encoding Na(V)1.6a (scn8aa) as a potential candidate for nav. Subsequent cloning of scn8aa from the two alleles of nav uncovered two missense mutations in Na(V)1.6a that eliminated channel activity when assayed heterologously. Furthermore, the injection of RNA encoding wild-type scn8aa rescued the nav mutant phenotype indicating that scn8aa was the causative gene of nav. In-vivo electrophysiological analysis of the touch-evoked escape circuit indicated that voltage-dependent inward current was decreased in mechanosensory neurons in mutants, but they were able to fire action potentials. Furthermore, tactile stimulation of mutants activated some neurons downstream of mechanosensory neurons but failed to activate the swim locomotor circuit in accord with the behavioral response of initial escape contractions but no swimming. Thus, mutant mechanosensory neurons appeared to respond to tactile stimulation but failed to initiate swimming. Interestingly fictive swimming could be initiated pharmacologically suggesting that a swim circuit was present in mutants. These results suggested that Na(V)1.6a was required for touch-induced activation of the swim locomotor network.
Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109-1048, USA.
Sean E
SE
Low
Weibin
W
Zhou
Ingxin
I
Choong
Louis
L
Saint-Amant
Shawn M
SM
Sprague
Hiromi
H
Hirata
Wilson W
WW
Cui
Richard I
RI
Hume
John Y
JY
Kuwada
D000200:Action Potentials / Q000235:genetics / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002490:Central Nervous System / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism; D002874:Chromosome Mapping; D005260:Female; D008297:Male; D008465:Mechanoreceptors / Q000166:cytology / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense / Q000235:genetics; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009415:Nerve Net / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000166:cytology / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology*; D013550:Swimming / Q000502:physiology*; D014110:Touch / Q000235:genetics / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology* / Q000254:growth & development / Q000502:physiology; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology*
D062557:NAV1.6 Voltage-Gated Sodium Channel; D015222:Sodium Channels; D029961:Zebrafish Proteins; C515010:scn8aa protein, zebrafish