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Mounting evidence suggests that synaptic connections are early pathological targets in many neurodegenerative diseases, including motor neuron disease (Wishart et al., J Neuropathol Exp Neurol 65, 2006). A better understanding of synaptic pathology is therefore likely to be critical in order to develop effective therapeutic strategies. We have investigated synaptic pathology in the Smn1–/–;SMN2 mouse model of type I Spinal Muscular Atrophy (SMA: a childhood form of motor neuron disease). We quantified synaptic innervation at the neuromuscular junction in a range of late-symptomatic (P5-P6) Smn1–/–;SMN2 muscle groups. Neonatal mice were killed by intraperitoneal injection of sodium pentabarbitol and the transversus abdominis (TA) and levator auris longus (LAL) muscles dissected. Post-synaptic acetylcholine receptors were labelled by exposure to rhodamine-conjugated α-bungarotoxin, and neurons were labelled immunocytochemically with anti-150 kDa neurofilament antibodies. Synaptic pathology was quantified using a combination of fluorescence and confocal microscopy. There was a significant reduction in the number of fully innervated motor endplates in the LAL (∼20% reduction) and the TA (∼40% reduction) in Smn1–/–;SMN2 mice. We observed the presence of abnormal axon branching that was most prevalent in areas where synapse loss was less advanced. Significant intra-muscle variation existed for both synaptic loss and abnormal axon branching, in agreement with previous studies from adult-onset motor neuron disease (ALS). We also show that synapse loss in the wasted mouse model of early-onset motor neuron degeneration (which has a phenotype remarkably similar to Smn1–/–;SMN2 mice) proceeds in advance of axonal pathology, suggesting the presence of a distal axonopathy. Visualisation of synaptic ultrastructure in wasted mice indicated that synapses were loss via a mechanism distinct from Wallerian degeneration. We conclude that synaptic loss is a major pathological event in conditions characterized by early-onset motor neuron degeneration, including SMA.
|Number of pages||1|
|Publication status||Published - Jan 2008|
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