Author:

Abstract:

The microtubule associated protein Tau is involved in many neuronal functions, particularly axonal vesicle transport and cytoskeletal plasticity. However, in many neuropathological conditions, protein Tau dislocates from the axons into the dendrites, where it forms insoluble hyper-phosphorylated neurofibrillary threads and tangles, a major pathological hallmark of AD. The progressive accumulation of tauopathy destabilizes the microtubular system and impairs axonal transport, putatively affecting synaptic plasticity and the neurocognitive functions that depend on it. In AD, tauopathy is distributed primarily to the entorhinal subregions, the hippocampus and neocortex. To investigate the consequences of Tau pathology on hippocampal synaptic plasticity, old (10 months) Tau.P301L mice (Terwel et al., 2005; Boekhoorn et al., 2006) were analysed for long-term depression (LTD) ex vivo. While basal synaptic transmission, paired pulse facilitation and LTP were unchanged in Tau.P301L mice, the late-phase LTD (>2 h) was absent, confirming our observations in a different transgenic tau mouse line (Ahmed et al. 2015). This L-LTD deficit is now demonstrated to be rescued by bath-application of the GSK3 antagonists SB216783 and indirubin-3-oxime, while these compounds blocked the intact, robust LTD in control mice. Interestingly, a similar rescue of impaired LTD in P301L was observed with the PP2A agonist sodium selenate, which had no effect on LTD in control mice. These data strengthen our hypothesis that the fine-tuned balance between PP2A and GSK3 activities is essential for proper neuronal functions and synaptic plasticity (Ahmed et al., 2015).