Spontaneous neural activity promotes axon growth in many types of developing neurons, including motoneurons. In motoneurons from a mouse model of spinal muscular atrophy (SMA), defects in axonal growth and presynaptic function correlate with a reduced frequency of spontaneous Ca2+ transients in axons which are mediated by N-type Ca2+ channels. To characterize the mechanisms that initiate spontaneous Ca2+ transients, we investigated the role of voltage-gated sodium channels (VGSCs). We found that low concentrations of the VGSC inhibitors tetrodotoxin (TTX) and saxitoxin (STX) reduce the rate of axon growth in cultured embryonic mouse motoneurons without affecting their survival. STX was 5- to 10-fold more potent than TTX and Ca2+ imaging confirmed that low concentrations of STX strongly reduce the frequency of spontaneous Ca2+ transients in somatic and axonal regions. These findings suggest that the NaV1.9, a VGSC that opens at low thresholds, could act upstream of spontaneous Ca2+ transients. qPCR from cultured and laser-microdissected spinal cord motoneurons revealed abundant expression of NaV1.9. NaV1.9 protein is preferentially localized in axons and growth cones. Suppression of NaV1.9 expression reduced axon elongation. Motoneurons from NaV1.9–/– mice showed the reduced axon growth in combination with reduced spontaneous Ca2+ transients in the soma and axon terminals. Thus, NaV1.9 function appears to be essential for activity-dependent axon growth, acting upstream of spontaneous Ca2+ elevation through voltage-gated calcium channels (VGCCs). NaV1.9 activation could therefore serve as a target for modulating axonal regeneration in motoneuron diseases such as SMA in which presynaptic activity of VGCCs is reduced.
Narayan Subramanian; Andrea Wetzel; Benjamin Dombert; Preeti Yadav; Steven Havlicek; Sibylle Jablonka; Mohammed A. Nassar; Robert Blum; Michael Sendtner
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