Defective Neuromuscular Junction Organization and Postnatal Myogenesis in Mice With Severe Spinal Muscular Atrophy

• Published in: Journal of neuropathology and experimental neurology Vol. 70; no. 6; pp. 444 - 461
• Main Authors: Dachs, Elisabet, Hereu, Marta, Piedrafita, Lídia, Casanovas, Anna, Calderó, Jordi, Esquerda, Josep E
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Association of Neuropathologists, Inc 01.06.2011; Lippincott Williams & Wilkins; Oxford University Press
• Subjects: Animals; Animals, Newborn; Apoptosis - genetics; Biological and medical sciences; Calcitonin Gene-Related Peptide - metabolism; Disease Models, Animal; Down-Regulation - genetics; Embryo, Mammalian; Humans; In Situ Nick-End Labeling - methods; Medical sciences; Mice; Mice, Transgenic; Muscle Development - genetics; Muscle Development - physiology; Muscle, Skeletal - pathology; Muscle, Skeletal - ultrastructure; Muscular Atrophy, Spinal - complications; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - mortality; Muscular Atrophy, Spinal - pathology; Neurology; Neuromuscular Junction - genetics; Neuromuscular Junction - growth & development; Neuromuscular Junction - pathology; Neuromuscular Junction - ultrastructure; Neuromuscular Junction Diseases - etiology; Neuromuscular Junction Diseases - metabolism; Neuromuscular Junction Diseases - pathology; rab3 GTP-Binding Proteins - metabolism; Survival of Motor Neuron 1 Protein - genetics; Survival of Motor Neuron 2 Protein - genetics; Tumors of the nervous system. Phacomatoses; Animal model; Neuromuscular diseases; Nervous system diseases; Rodentia; Spinal amyotrophy; Motor neuron; Motoneuron; Striated muscle; Neuromuscular junction; Myogenesis; Skeletal muscle; Spinal muscular atrophy; Vertebrata; Mammalia; Postnatal; Mouse; Animal; Central nervous system disease; Degenerative disease; Mouse model; Spinal cord disease; Apoptosis; Macrophage
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1097/NEN.0b013e31821cbd8b

A detailed pathologic analysis was performed on Smn;SMN2 mice as a mouse model for human type I spinal muscular atrophy (SMA). We provide new data concerning changes in the spinal cord, neuromuscular junctions and muscle cells, and in the organs of the immune system. The expression of 10 synaptic proteins was analyzed in 3-dimensionally reconstructed neuromuscular junctions by confocal microscopy. In addition to defects in postsynaptic occupancy, there was a marked reduction in calcitonin gene-related peptide and Rab3A in the presynaptic motor terminals of some, but not all, of the skeletal muscles analyzed. Defects in the organization of presynaptic nerve terminals were also detected by electron microscopy. Moreover, degenerative changes in muscle cells, defective postnatal muscle growth, and prominent muscle satellite cell apoptosis were also observed. All of these changes occurred in the absence of massive loss of spinal cord motoneurons. On the other hand, astroglia, but not microglia, increased in the ventral horn of newborn SMA mice. In skeletal muscles, the density of interstitial macrophages was significantly reduced, and monocyte chemotactic protein-1 was downregulated. These findings raise questions regarding the primary contribution of a muscle cell defect to the SMA phenotype.