Abstract
Lower motor neuron dysfunction is one of the most debilitating motor conditions. In this regard, transgenic mouse models of various lower motor neuron dysfunctions provide insight into the mechanisms underlying these pathologies and can also aid the development of new therapies. Viral-mediated gene therapy can take advantage of the muscle-motor neuron topographical relationship to shuttle therapeutic genes into specific populations of motor neurons in these mouse models. In this context, motor end plates (MEPs) are highly specialized regions on the skeletal musculature that offer direct access to the pre-synaptic nerve terminals, henceforth to the spinal cord motor neurons. The aim of this study was two-folded. First, it was to characterize the exact position of the MEP regions for several muscles of the mouse forelimb using acetylcholinesterase histochemistry. This MEP-muscle map was then used to guide a series of intramuscular injections of Fluoro-Gold (FG) in order to characterize the distribution of the innervating motor neurons. This analysis revealed that the MEPs are typically organized in an orthogonal fashion across the muscle fibers and extends throughout the full width of each muscle. Furthermore, targeting the full length of the MEP regions gave rise labeled motor neurons that are organized into columns spanning through more spinal cord segments than previously reported. The present analysis suggests that targeting the full width of the muscles’ MEP regions with FG increases the somatic availability of the tracer. This process ensures a greater uptake of the tracer by the pre-synaptic nerve terminals, hence maximizing the labeling in spinal cord motor neurons. This investigation should have positive implications for future studies involving the somatic delivery of therapeutic genes into motor neurons for the treatment of various motor dysfunctions.
Highlights
Knowledge regarding the organization of the lower motor neuron system has significantly developed through the work of Sherrington (1892), Romanes (1941, 1946, 1951), and Rexed (1954)
MOTOR END PLATE DELINEATION Overall, for each muscle the location of the motor end plates (MEPs) region was similar between animals
The MEP regions can be seen as extending across the full width of the muscles, passing through, but not limited to the region commonly referred to as the muscle “belly” (Figures 1A–C)
Summary
Knowledge regarding the organization of the lower motor neuron system has significantly developed through the work of Sherrington (1892), Romanes (1941, 1946, 1951), and Rexed (1954). The Cu/Zn superoxide dismutase type-1 (SOD-1) mouse model was developed in order to further understand the etiology and pathogenesis of a subtype of amyotrophic lateral sclerosis (Gurney et al, 1994; Wong et al, 1995; Raoul et al, 2005; Zhong et al, 2009; Towne et al, 2010; Riboldi et al, 2011) This is the case for the survival motor neuron 1 (SMN) knockout mouse model of spinal muscular atrophy (SMA) (Hsieh-Li et al, 2000). Viral-mediated gene therapy can take advantage of the musclemotor neuron topographical relationship to retrogradely shuttle therapeutic genes into specific populations of motor neurons
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