Davis, K; (2008) Evidence of disease resistance in cholinergic synapses on spinal motor neurons in a mouse model of amyotrophic lateral sclerosis. Doctoral thesis , UCL (University College London).

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Abstract

Transgenic mice with a mutant human Cu/Zn superoxide dismutase 1 (S0D1) gene have provided a valuable model of the human disease amyotrophic lateral sclerosis (ALS). ALS is caused by the progressive degeneration of motor neurons (MNs) in the motor cortex, brainstem and spinal cord, which involves a progressive decrease in the number of synapses contacting MNs. Previous studies have indicated that the cholinergic C-type synapse exhibits an increase in size and number on spinal MNs in the clinical stages of human ALS and animal models of ALS, which is contrary to the extensive general synaptic loss seen in the disease. This study examined the frequency and size of cholinergic, putative C-type synapses contacting ventral horn motor neurons in the 93 lumbar spinal cord of clinically affected Tg mice carrying a Gly -> Ala (G93A) mutant SOD1 gene found in familial ALS (fALS). General synaptic loss was also assessed in order to provide a base comparison with cholinergic synapse frequency. Immunocytochemical analyses were performed for synaptophysin (SP) and vesicular acetylcholine transporter (VAChT) proteins in order to measure general synapse frequency and cholinergic synapse frequency, respectively. Mice were examined at an early presymptomatic stage (aged 9-11 weeks), a transitional stage (aged 13 weeks) and a late end-stage (aged 16-20weeks). Transgenic mice exhibited a much larger progressive reduction of the immunoreactivity for SP compared to Wt mice. In contrast, immunostaining for VAChT revealed similar levels of immunoreactivity at late end-stage in both Wt and Tg mice. Measuring the widths of VAChT-immunoreactive synapses showed a significantly larger increase in synapse width in Tg mice from early stage to late stage compared to Wt mice. These results provide evidence supporting previous electron microscopy findings indicating that synapses, defined ultrastructurally as C-type, increase in frequency and size on surviving MNs at a late clinical stage in humans and mice. The ability of putative C-synapses to resist general synaptic loss may provide a defense mechanism for spinal MNs in the present model of fALS.

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