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Abstract
During development, motoneurons experience significant changes in their size and in the number and strength of connections that they receive, which requires adaptive changes in their passive and active electrical properties. Even after reaching maturity, motoneurons continue to adjust their intrinsic excitability and synaptic activity for proper functioning of the sensorimotor circuit in accordance with physiological demands. Likewise, if some elements of the circuit become dysfunctional, the system tries to compensate for the alterations to maintain appropriate function. In Spinal Muscular Atrophy (SMA), a severe motor disease, spinal motoneurons receive less excitation from glutamatergic sensory fibers and interneurons and are electrically hyperexcitable. Currently, the origin and relationship among these alterations are not completely established. In this study, we investigated whether Survival of Motor Neuron (SMN), the ubiquitous protein defective in SMA, regulates the excitability of motoneurons before and after the establishment of the synaptic contacts. To this end, we performed patch-clamp recordings in embryonic spinal motoneurons forming complex synaptic networks in primary cultures, and in differentiated NSC-34 motoneuron-like cells in the absence of synaptic contacts. Our results show that in both conditions, Smn-deficient cells displayed lower action potential threshold, greater action potential amplitudes, and larger density of voltage-dependent sodium currents than cells with normal Smn-levels. These results indicate that Smn participates in the regulation of the cell-autonomous excitability of motoneurons at an early stage of development. This finding may contribute to a better understanding of motoneuron excitability in SMA during the development of the disease.
Highlights
Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality (Sugarman et al, 2012), is an autosomal recessive monogenic disease characterized by neuromuscular dysfunction, loss of motoneurons and paralysis
Reduced expression of Smn in non-neuronal cells may contribute to the pathogenesis of SMA; for example, the interaction between astrocytes and motoneurons, which is known to contribute to formation and maintenance of synaptic contacts, are diminished in SMA mouse models (Rindt et al, 2015; Zhou et al, 2016)
The transduction efficiency is excellent (GFP-positive cells) with significant Smn protein level reduction at 3 days of interference, which is maintained after 9 days (Garcera et al, 2011)
Summary
Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality (Sugarman et al, 2012), is an autosomal recessive monogenic disease characterized by neuromuscular dysfunction, loss of motoneurons and paralysis. It is caused by reduced levels of the survival of motor neuron protein (SMN; Lefebvre et al, 1995, 1997; Crawford and Pardo, 1996), which is a ubiquitous multifunctional protein that localizes to the cell nucleus and soma and participates in the assembly of the splicing machinery (Gubitz et al, 2004; Battle et al, 2006). Reduced expression of Smn in non-neuronal cells may contribute to the pathogenesis of SMA; for example, the interaction between astrocytes and motoneurons, which is known to contribute to formation and maintenance of synaptic contacts, are diminished in SMA mouse models (Rindt et al, 2015; Zhou et al, 2016)
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