Delayed synaptic degeneration in the CNS of

These authors contributed equally to this work Therapies that might delay degeneration of synapses offer an appealing strategy for treatment of neuro-degenerative 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 relevantmechanisms.Here, we used quantitative and serial section electronmicroscopy to find outwhether 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 degen-eration 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