title: Pro-aggregant Tau impairs mossy fiber plasticity due to structural changes and Ca(++) dysregulation.
abstract: BACKGROUND
  We used an inducible mouse model expressing the Tau repeat domain with the pro-aggregant mutation ΔK280 to analyze presynaptic Tau pathology in the hippocampus.
  
  
  RESULTS
  Expression of pro-aggregant Tau(RDΔ) leads to phosphorylation, aggregation and missorting of Tau in area CA3. To test presynaptic pathophysiology we used electrophysiology in the mossy fiber tract. Synaptic transmission was severely disturbed in pro-aggregant Tau(RDΔ) and Tau-knockout mice. Long-term depression of the mossy fiber tract failed in pro-aggregant Tau(RDΔ) mice. We observed an increase in bouton size, but a decline in numbers and presynaptic markers. Both pre-and postsynaptic structural deficits are preventable by inhibition of Tau(RDΔ) aggregation. Calcium imaging revealed progressive calcium dysregulation in boutons of pro-aggregant Tau(RDΔ) mice. In N2a cells we observed this even in cells without tangle load, whilst in primary hippocampal neurons transient Tau(RDΔ) expression alone caused similar Ca(++) dysregulation. Ultrastructural analysis revealed a severe depletion of synaptic vesicles pool in accordance with synaptic transmission impairments.
  
  
  CONCLUSIONS
  We conclude that oligomer formation by Tau(RDΔ) causes pre- and postsynaptic structural deterioration and Ca(++) dysregulation which leads to synaptic plasticity deficits.
authors: Jochen Martin
authors: JM
authors: Decker
authors: Lars
authors: L
authors: Krüger
authors: Astrid
authors: A
authors: Sydow
authors: Shanting
authors: S
authors: Zhao
authors: Michael
authors: M
authors: Frotscher
authors: Eckhard
authors: E
authors: Mandelkow
authors: Eva-Maria
authors: EM
authors: Mandelkow
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D004594:Electrophysiology; D006624:Hippocampus / Q000502:physiology; D017774:Long-Term Potentiation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D019599:Mossy Fibers, Hippocampal / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*; D016875:tau Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D002118:Calcium