Researchers from Germany described the motor circuit pathology in 3 mouse models of spinal muscular atrophy (SMA). The findings can provide a knowledge base that can help researchers better tailor their studies for SMA in the future, they said.
The 3 models in question were the SMNΔ7, Taiwanese, and Smn2B/- mice, which are the mouse models most widely used to study SMA. Of these, the first 2 lines are considered models of severe disease because they only survive for 2 weeks, while the third is considered a milder disease model, with animals surviving for up to 4 weeks.
However, there has never been a direct comparison in terms of the pathology of motor circuits between these models.
Here, a team of researchers led by Christian M. Simon, PhD, from Carl-Ludwig-Institute for Physiology at Leipzig University in Germany investigated the phenotypical, morphological, functional, and molecular changes that occurred in the spinal motor circuits of these 3 models to help identify the shared and distinct features of disease pathology.
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They found that the SMNΔ7 model showed vast motor circuit defects, which included the degeneration of motor neurons, spinal excitatory synapses, and neuromuscular junctions.
The Taiwanese model, on the other hand, exhibited very mild motor neuron pathology. However, the animals had an early central synaptic loss.
Finally, the Smn2B/- model showed strong central excitatory synapses pathology. In these animals, neuromuscular junction defects preceded late-onset p53-dependent motor neuron death.
The researchers concluded that these pathological events correlated with the dysregulation of mRNA splicing dependent on survival motor neuron (SMN) protein. They also noted that “central excitatory synaptopathy is the most conserved feature of SMA pathology.”
“Our study reveals common and distinct features of motor circuit pathology across mouse lines, underlining the strength and limitations of each mouse model,” they wrote.
The study is available as a journal pre-proof in iScience.
Buettner JM, Longang JKS, Gerstner F, et al. Central synaptopathy is the most conserved feature of motor circuit pathology across SMA mouse models. iScience. Published online October 30, 2021. doi:10.1016/j.isci.2021.103376