Abstract
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 Ca(2+) transients in axons which are mediated by N-type Ca(2+) channels. To characterize the mechanisms that initiate spontaneous Ca(2+) 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 Ca(2+) imaging confirmed that low concentrations of STX strongly reduce the frequency of spontaneous Ca(2+) transients in somatic and axonal regions. These findings suggest that the Na(V)1.9, a VGSC that opens at low thresholds, could act upstream of spontaneous Ca(2+) transients. qPCR from cultured and laser-microdissected spinal cord motoneurons revealed abundant expression of Na(V)1.9. Na(V)1.9 protein is preferentially localized in axons and growth cones. Suppression of Na(V)1.9 expression reduced axon elongation. Motoneurons from Na(V)1.9(-/-) mice showed the reduced axon growth in combination with reduced spontaneous Ca(2+) transients in the soma and axon terminals. Thus, Na(V)1.9 function appears to be essential for activity-dependent axon growth, acting upstream of spontaneous Ca(2+) elevation through voltage-gated calcium channels (VGCCs). Na(V)1.9 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.
Highlights
Axons of developing motoneurons grow long distances before they make synaptic contacts with their target tissue, the skeletal muscle [1]
These findings suggest that the NaV1.9, a voltage-gated sodium channels (VGSCs) that opens at low thresholds, could act upstream of spontaneous Ca21 transients. qPCR from cultured and lasermicrodissected spinal cord motoneurons revealed abundant expression of NaV1.9
To investigate whether VGSCs are involved in activitydependent axon elongation, we tested the effects of the sodium-channel inhibitors tetrodotoxin (TTX) and saxitoxin (STX) in cultures of isolated spinal motoneurons
Summary
Axons of developing motoneurons grow long distances before they make synaptic contacts with their target tissue, the skeletal muscle [1]. During this period, motoneurons depend on neurotrophic factors for their survival (2 – 4). Cultured embryonic motoneurons need neurotrophic factors for survival and neurite growth, allowing the analysis of signaling pathways for axon elongation and differentiation of presynaptic structures within axonal growth cones (1,5 – 7). Spontaneous Ca2+ transients in axons and axonal growth cones contribute to axon extension and presynaptic differentiation [17].
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