Pro-aggregant Tau impairs mossy fiber plasticity due to structural changes and Ca++ dysregulation

Abstract

IntroductionWe used an inducible mouse model expressing the Tau repeat domain with the pro-aggregant mutation ΔK280 to analyze presynaptic Tau pathology in the hippocampus.ResultsExpression of pro-aggregant TauRDΔ 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 TauRDΔ and Tau-knockout mice. Long-term depression of the mossy fiber tract failed in pro-aggregant TauRDΔ 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 TauRDΔ aggregation. Calcium imaging revealed progressive calcium dysregulation in boutons of pro-aggregant TauRDΔ mice. In N2a cells we observed this even in cells without tangle load, whilst in primary hippocampal neurons transient TauRDΔ expression alone caused similar Ca++ dysregulation. Ultrastructural analysis revealed a severe depletion of synaptic vesicles pool in accordance with synaptic transmission impairments.ConclusionsWe conclude that oligomer formation by TauRDΔ causes pre- and postsynaptic structural deterioration and Ca++ dysregulation which leads to synaptic plasticity deficits.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0193-3) contains supplementary material, which is available to authorized users.

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

“…However, both hTau‐A152T and hTau‐WT mice had age‐dependent increases in synaptic transmission strength and decreases in paired‐pulse facilitation at the mossy fiber/CA3 pyramidal cell synapse. In contrast, synaptic transmission and facilitation were unaltered or reduced at this synapse in hTau mice bearing FTDP‐17 mutations (P301L and ∆K280) that strongly promote tau aggregation 36, 78, 79, 80, 81. Whether and how these phenotypic differences relate to specific conformations and assemblies of tau 82 remains to be determined.…”

Tau neurotoxicity and rescue in animal models of human Tauopathies

“…TKO mice displayed a selective deficit in long-term depression (LTD) at the CA1 synapse [46,47]. By contrast, this was not the case for LTD evoked at the mossy fibers (mf) in the CA3 region, where LTD was not altered in TKO mice [41].…”

“…Another line expressing aggregation-prone Tau (mutation DK280) alters presynaptic morphology (e.g. depletion of synaptic vesicle pool) and function of the mossy fibers, which also affected postsynaptic neurons [41]. Mice expressing the V337M mutant of Tau showed an NMDA receptor hypofunction, and pathology could be prevented by the NMDAR co-agonist cycloserine [42].…”

Motor Deficit in a Tauopathy Model Is Induced by Disturbances of Axonal Transport Leading to Dying-Back Degeneration and Denervation of Neuromuscular Junctions

“…A recent study also pointed to disturbances at the presynaptic level in mossy fibers in the hippocampus in a tauopathy model. 47 To conclude, we show in this study that expression of a human mutant tau protein in the motoneurons and their processes leads to dying-back axonopathy and an early alteration of synaptophysin distribution in motor nerve terminals from 1 month in Tg30 mice. An axonopathy develops during the following months, characterized by accumulation of aggregates and organelles.…”