Journal Article

Improvement of Neuromuscular Synaptic Phenotypes without Enhanced Survival and Motor Function in Severe Spinal Muscular Atrophy Mice Selectively Rescued in Motor Neurons

Sumner, Charlotte J., Seaberg, Bonnie, Martinez, Tara L., Rimer, Mendell, Kong, Lingling, Paez-Colasante, Ximena

2013

Overview

In the inherited childhood neuromuscular disease spinal muscular atrophy (SMA), lower motor neuron death and severe muscle weakness result from the reduction of the ubiquitously expressed protein survival of motor neuron (SMN). Although SMA mice recapitulate many features of the human disease, it has remained unclear if their short lifespan and motor weakness are primarily due to cell-autonomous defects in motor neurons. Using Hb9(Cre) as a driver, we selectively raised SMN expression in motor neurons in conditional SMAΔ7 mice. Unlike a previous study that used choline acetyltransferase (ChAT(Cre+) ) as a driver on the same mice, and another report that used Hb9(Cre) as a driver on a different line of conditional SMA mice, we found no improvement in survival, weight, motor behavior and presynaptic neurofilament accumulation. However, like in ChAT(Cre+) mice, we detected rescue of endplate size and mitigation of neuromuscular junction (NMJ) denervation status. The rescue of endplate size occurred in the absence of an increase in myofiber size, suggesting endplate size is determined by the motor neuron in these animals. Real time-PCR showed that the expression of spinal cord SMN transcript was sharply reduced in Hb9(Cre+) SMA mice relative to ChAT(Cre+) SMA mice. This suggests that our lack of overall phenotypic improvement is most likely due to an unexpectedly poor recombination efficiency driven by Hb9(Cre) . Nonetheless, the low levels of SMN were sufficient to rescue two NMJ structural parameters indicating that these motor neuron cell autonomous phenotypes are very sensitive to changes in motoneuronal SMN levels. Our results directly suggest that even those therapeutic interventions with very modest effects in raising SMN in motor neurons may provide mitigation of neuromuscular phenotypes in SMA patients.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acetyltransferase / Animals / Atrophy / Cell death / Cell survival / Children / Choline / Choline O-acetyltransferase / Defects / Denervation / DNA Primers - genetics / Gene expression / Genetic aspects / Genotype / Health aspects / Life span / Medicine / Mice / Mitigation / Motor Endplate - metabolism / Motor Endplate - physiology / Motor neurons / Motor Neurons - physiology / Muscles / Muscular Atrophy, Spinal - physiopathology / Muscular Atrophy, Spinal - therapy / Neurology / Neuromuscular diseases / Neuromuscular junctions / Neurons / Neurosciences / Parameter sensitivity / Pediatric diseases / Phenotype / Phenotypes / Proteins / Real-Time Polymerase Chain Reaction / Recombination / Rodents / SMN Complex Proteins - metabolism / SMN protein / Spinal cord / Spinal muscular atrophy / Survival / Survival Analysis / Synapses - physiology / Therapeutic applications / Transcription