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The Tau/A152T mutation, a risk factor for frontotemporal‐spectrum disorders, leads to NR 2B receptor‐mediated excitotoxicity
Author(s) -
Decker Jochen Martin,
Krüger Lars,
Sydow Astrid,
Dennissen Frank JA,
Siskova Zuzana,
Mandelkow Eckhard,
Mandelkow EvaMaria
Publication year - 2016
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201541439
Subject(s) - excitotoxicity , mutation , genetics , receptor , neuroscience , biology , gene , glutamate receptor
We report on a novel transgenic mouse model expressing human full‐length Tau with the Tau mutation A152T ( hT au AT ), a risk factor for FTD ‐spectrum disorders including PSP and CBD . Brain neurons reveal pathological Tau conformation, hyperphosphorylation, mis‐sorting, aggregation, neuronal degeneration, and progressive loss, most prominently in area CA 3 of the hippocampus. The mossy fiber pathway shows enhanced basal synaptic transmission without changes in short‐ or long‐term plasticity. In organotypic hippocampal slices, extracellular glutamate increases early above control levels, followed by a rise in neurotoxicity. These changes are normalized by inhibiting neurotransmitter release or by blocking voltage‐gated sodium channels. CA 3 neurons show elevated intracellular calcium during rest and after activity induction which is sensitive to NR 2B antagonizing drugs, demonstrating a pivotal role of extrasynaptic NMDA receptors. Slices show pronounced epileptiform activity and axonal sprouting of mossy fibers. Excitotoxic neuronal death is ameliorated by ceftriaxone, which stimulates astrocytic glutamate uptake via the transporter EAAT 2/ GLT 1. In summary, hT au AT causes excitotoxicity mediated by NR 2B‐containing NMDA receptors due to enhanced extracellular glutamate.