Delayed synaptic degeneration in the CNS of Wlds mice after cortical lesion
1 Centre for Neuroscience Research University of Edinburgh, Edinburgh, UK 2 Division of Veterinary Biomedical Sciences University of Edinburgh, Edinburgh, UK 3 Centre for Integrative Physiology University of Edinburgh, Edinburgh, UK
Correspondence to: Dr Thomas H. Gillingwater, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UK E-mail: T.Gillingwater{at}ed.ac.uk
Therapies that might delay degeneration of synapses offer an appealing strategy for treatment of neurodegenerative diseases, including Alzheimer's disease and related dementias, prion diseases, schizophrenia and amyotrophic lateral sclerosis. Analysis of mouse mutants provides one possible avenue towards identifying relevant mechanisms. Here, we used quantitative and serial section electron microscopy to find out whether the onset and time course of pre-synaptic nerve terminal degeneration is delayed in the striatum of Wallerian degeneration slow (Wlds) mutant mice. Synaptic degeneration was observed within 48 h of cortical ablation in wild-type mice but was delayed by approximately 1 week in Wlds mice. However, the morphological characteristics of degenerating nerve terminals in wild-type and Wlds mice were indistinguishable, in contrast to the differences reported previously in studies of the PNS. Surprisingly, the delayed onset of synaptic degeneration was accompanied by an increased incidence of complex synaptic morphologies on post-synaptic spines in the denervated WldS striatum indicating an enhanced plastic response at both injured and uninjured synapses. The data suggest that targeting Wallerian-like mechanisms of synaptic degeneration could lead to the development of new therapies for the treatment of CNS disorders where synapse loss is a primary feature.
Key Words: Synapse; neurodegeneration; neuroprotection; brain; Alzheimer's disease; electron microscopy
Abbreviations: GFAP, glial fibrillary acidic protein; LCP, large complex/perforated; WldS, Wallerian degeneration slow
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Received September 30, 2005. Revised January 31, 2006. Accepted March 27, 2006.
*These authors contributed equally to this work
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