Society for Neuroscience Annual Meeting, Date: 2016/11/12 - 2016/11/16, Location: San Diego, CA, USA
Author:
Abstract:
In several neurodegenerative disorders including Alzheimer’s disease (AD) and Tauopathies, synapse loss precedes neuronal death. A very sensitive readout of synaptic deficits in murine models of these diseases is monitoring alterations in activity-dependent synaptic plasticity, e.g., long-term potentiation (LTP) or long-term depression (LTD). In the past, LTP was mostly employed to detect functional disturbances during the progression of pathology, but LTD was hardly considered. We have recently introduced LTD as a complementary sensitive read-out. This is in line with several reports that link LTD with cognitive flexibility, which is deteriorated in many AD patients. Here we examined the consequences of Tau and GSK3β pathology on hippocampal synaptic plasticity using LTD in the hippocampal CA1-region of 10- 12 month-old mice as a model. We compared the following mouse models: (i) Tau.P301L that express the human familial tauopathy mutant; (ii) biAT that are bigenic mice carrying human mutant APP.V717I and Tau.P301L; (iii) GSK3βn-/- mice in which GSK3β is specifically knocked-out in neurons; (iv) GSK3β.S9A with a constitutive overactive GSK3β by replacing the wild-type serine at position 9 by alanine and; (iv) biGT mice that are bigenic mice that combine mutant Tau.P301L and GSK3β.S9A (Terwel et al., 2005, 2008; Dewachter et al., 2009; Jaworski et al., 2011). While basal synaptic transmission and paired pulse facilitation were unaffected in all but biGT mice, late-phase LTD (>2 h) was impaired in Tau.P301L, biAT, GSK3βn-/- and biGT mice. Application of the GSK3 antagonist SB216783 rescued this deficit only in Tau.P301L and biAT mice, but not in biGT animals. In GSK3β.S9A, SB216783 blocked the robust LTD to the same extent as in WT mice. Interestingly, a similar rescue of impaired LTD was obtained with the PP2A agonist sodium selenate in Tau.P301L, biAT and biGT mice. Noteworthy, selenate had no effect on LTD in WT control mice. The combined data-sets further strengthen our hypothesis that a fine-tuned balance between PP2A and GSK3 activity is essential for proper neuronal functions and synaptic plasticity (Ahmed et al., 2015).