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

Jochen Martin Decker,Michael Frotscher,Eva-Maria Mandelkow,Shanting Zhao,Eckhard Mandelkow,Lars Krüger,Astrid Sydow

doi:10.1186/s40478-015-0193-3

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.

Highlights

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
We conclude that oligomer formation by TauRDΔ causes pre- and postsynaptic structural deterioration and Ca++ dysregulation which leads to synaptic plasticity deficits
Endogenous Tau becomes phosphorylated and aggregated in area CA3 of the hippocampus due to expression of the human Tau repeat domain ΔK280 The “mossy fiber pathway” denotes axonal projections from dentate gyrus (DG) granule cells to area CA3 of the hippocampus, where “giant” boutons innervate thorny excrescences at CA3 pyramidal cell dendrites and interneurons. These projections lying within the hippocampal layer stratum lucidum (s.l., Figure 1a) are prone to pathological Tau hyperphosphorylation and aggregation in a FTDP-17 based mouse model overexpressing the repeat domain of Tau with the mutation ΔK280 (TauRDΔ) in the forebrain [7,8]

Summary

Introduction

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. Most electrophysiological studies investigated Tau-related postsynaptic changes in area CA1 of the hippocampus [4,5,6] It became increasingly obvious from animal models expressing mutant Tau that Tau pathology. Tau becomes highly phosphorylated and missorted from its normal axonal localization into the somatodendritic compartment, which leads to the retraction of mossy fibers from CA3 postsynapses [16]. This process is reversible and suggests a physiological role of Tau in mossy fiber plasticity. Tau plays an important role in mossy fiber reorganization during development [17], and Tau is involved in the pathological sprouting of mossy fibers induced by kainate injection to generate epileptic seizures [18]

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Conclusion