title: The role of activity in synaptic degeneration in a protein misfolding disease, prion disease.
abstract: In chronic neurodegenerative diseases associated with aggregates of misfolded proteins (such as Alzheimer's, Parkinson's and prion disease), there is an early degeneration of presynaptic terminals prior to the loss of the neuronal somata. Identifying the mechanisms that govern synapse degeneration is of paramount importance, as cognitive decline is strongly correlated with loss of presynaptic terminals in these disorders. However, very little is known about the processes that link the presence of a misfolded protein to the degeneration of synapses. It has been suggested that the process follows a simple linear sequence in which terminals that become dysfunctional are targeted for death, but there is also evidence that high levels of activity can speed up degeneration. To dissect the role of activity in synapse degeneration, we infused the synaptic blocker botulinum neurotoxin A (BoNT/A) into the hippocampus of mice with prion disease and assessed synapse loss at the electron microscopy level. We found that injection of BoNT/A in naïve mice caused a significant enlargement of excitatory presynaptic terminals in the hippocampus, indicating transmission impairment. Long-lasting blockade of activity by BoNT/A caused only minimal synaptic pathology and no significant activation of microglia. In mice with prion disease infused with BoNT/A, rates of synaptic degeneration were indistinguishable from those observed in control diseased mice. We conclude that silencing synaptic activity neither prevents nor enhances the degree of synapse degeneration in prion disease. These results challenge the idea that dysfunction of synaptic terminals dictates their elimination during prion-induced neurodegeneration.
authors: National Research Council Neuroscience Institute, Pisa, Italy. caleo@in.cnr.it
authors: Matteo
authors: M
authors: Caleo
authors: Laura
authors: L
authors: Restani
authors: Eleonora
authors: E
authors: Vannini
authors: Zuzana
authors: Z
authors: Siskova
authors: Hussain
authors: H
authors: Al-Malki
authors: Ruth
authors: R
authors: Morgan
authors: Vincent
authors: V
authors: O'Connor
authors: V Hugh
authors: VH
authors: Perry
mesh_terms: D000818:Animals; D019274:Botulinum Toxins, Type A / Q000494:pharmacology*; D020868:Gene Silencing; D006624:Hippocampus / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D008854:Microscopy, Electron / Q000379:methods; D008959:Models, Neurological; D019636:Neurodegenerative Diseases / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism*; D017510:Protein Folding; D057165:Proteostasis Deficiencies / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
chemical_list: D019274:Botulinum Toxins, Type A; C545476:incobotulinumtoxinA