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The Journal of Neuroscience, January 21, 2009, 29(3):842-851; doi:10.1523/JNEUROSCI.4434-08.2009

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Neurobiology of Disease
Impaired Synaptic Vesicle Release and Immaturity of Neuromuscular Junctions in Spinal Muscular Atrophy Mice

Lingling Kong,¹ Xueyong Wang,² Dong W. Choe,¹ Michelle Polley,¹ Barrington G. Burnett,³ Marta Bosch-Marcé,¹ John W. Griffin,¹ Mark M. Rich,² and Charlotte J. Sumner¹

¹Department of Neurology, Johns Hopkins University, Baltimore, Maryland 21287, ²Department of Neurology, Neuroscience, Cell Biology, and Physiology, Wright State University, Dayton, Ohio 45435, and ³Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892

Correspondence should be addressed to Charlotte J. Sumner, Department of Neurology, Johns Hopkins University, 600 North Wolfe Street, Meyer 5-119b, Baltimore, MD 21287. Email: csumner1{at}jhmi.edu

The motor neuron disease spinal muscular atrophy (SMA) causes profound muscle weakness that most often leads to early death. At autopsy, SMA is characterized by loss of motor neurons and muscle atrophy, but the initial cellular events that precipitate motor unit dysfunction and loss remain poorly characterized. Here, we examined the function and corresponding structure of neuromuscular junction (NMJ) synapses in a mouse model of severe SMA (hSMN2/delta7SMN/mSmn–/–). Surprisingly, most SMA NMJs remained innervated even late in the disease course; however they showed abnormal synaptic transmission. There was a two-fold reduction in the amplitudes of the evoked endplate currents (EPCs), but normal spontaneous miniature EPC (MEPC) amplitudes. These features in combination indicate reduced quantal content. SMA NMJs also demonstrated increased facilitation suggesting a reduced probability of vesicle release. By electron microscopy, we found a decreased density of synaptic vesicles that is likely to contribute to the reduced release probability. In addition to presynaptic defects, there were postsynaptic abnormalities. EPC and MEPC decay time constants were prolonged because of a slowed switch from the fetal acetylcholine receptor (AChR) -subunit to the adult -subunit. There was also reduced size of AChR clusters and small myofibers, which expressed an immature pattern of myosin heavy chains. Together these results indicate that impaired synaptic vesicle release at NMJs in severe SMA is likely to contribute to failed postnatal maturation of motor units and muscle weakness.

Key words: spinal muscular atrophy; motor neuron; neuromuscular junction; synapse; synaptic vesicle; acetylcholine receptor

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Received Sept. 16, 2008; revised Nov. 24, 2008; accepted Dec. 8, 2008.

Correspondence should be addressed to Charlotte J. Sumner, Department of Neurology, Johns Hopkins University, 600 North Wolfe Street, Meyer 5-119b, Baltimore, MD 21287. Email: csumner1{at}jhmi.edu

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