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Defective Ca²⁺ channel clustering in axon terminals disturbs excitability in motoneurons in spinal muscular atrophy

Institute for Clinical Neurobiology, University of Wuerzburg, Wuerzburg D-97078, Germany

Correspondence to Michael Sendtner: Sendtner_M{at}klinik.uni-wuerzburg.de

Proximal spinal muscular atrophy (SMA) is a motoneuron disease for which there is currently no effective treatment. In animal models of SMA, spinal motoneurons exhibit reduced axon elongation and growth cone size. These defects correlate with reduced ß-actin messenger RNA and protein levels in distal axons. We show that survival motoneuron gene (Smn)–deficient motoneurons exhibit severe defects in clustering Ca_v2.2 channels in axonal growth cones. These defects also correlate with a reduced frequency of local Ca²⁺ transients. In contrast, global spontaneous excitability measured in cell bodies and proximal axons is not reduced. Stimulation of Smn production from the transgenic SMN2 gene by cyclic adenosine monophosphate restores Ca_v2.2 accumulation and excitability. This may lead to the development of new therapies for SMA that are not focused on enhancing motoneuron survival but instead investigate restoration of growth cone excitability and function.

Abbreviations used in this paper: 8-CPT-cAMP, 8-(4-chlorophenylthio)–3',5' cAMP; ANOVA, analysis of variance; CTX, -conotoxin MVIIA; E, embryonic day; NMJ, neuromuscular junction; SMA, spinal muscular atrophy; Smn, survival motoneuron gene; STED, stimulated emission depletion; TRPC, transient receptor potential ion channel; TTX, tetrodotoxin; VGCC, voltage-gated Ca²⁺ channel.

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