Rescue of impaired lateephase long-term depression in a tau transgenic mouse model Tariq Ahmed a , David Blum b, c, d , Sylvie Burnouf b, c, e , Dominique Demeyer b, c , Valérie Buée-Scherrer b, c, d , Rudi D’Hooge a , Luc Buée b, c, d , Detlef Balschun a, * a Laboratory of Biological Psychology, University of Leuven, Leuven, Belgium b Université Lille-Nord de France, UDSL, Lille, France c Inserm UMR837, Jean-Pierre Aubert Research Centre, Lille, France d CHRU-Lille, Lille, France e Max-Planck Institute for Biology of Ageing, Köln, Germany article info Article history: Received 2 July 2013 Received in revised form 1 September 2014 Accepted 17 September 2014 Available online 28 September 2014 Keywords: Long-term depression LTD Synaptic plasticity Alzheimer’s disease Tauopathy Glycogen synthase kinase-3 Protein-phosphatase 2A Sodium selenate SB216763 Okadaic acid Hippocampus CA1-region abstract Cognitive decline, the hallmark of Alzheimer’s disease, and accompanying neuropsychiatric symptoms share dysfunctions of synaptic processes as a common cellular pathomechanism. Long-term potentiation has proven to be a sensitive tool for the “diagnosis” of such synaptic dysfunctions. Much less, however, is known about how long-term depression (LTD), an alternative mechanism for the storage of memory, is affected by Alzheimer’s disease progression. Here, we demonstrate that impaired late LTD (>3 hours) in THY-Tau22 mice can be rescued by either inhibition of glycogen synthase kinase-3 (GSK3b) activity or by application of the protein-phosphatase 2A agonist selenate. In line with these findings, we observed increased phosphorylation of GSK3b at Y216 and reduced total phosphatase activity in biochemical as- says of hippocampal tissue of THY-Tau22 mice. Interestingly, LTD induction and pharmacologic inhibition of GSK3b appeared to downregulate GSK3ß activity via a marked upregulation of phosphorylation at the inhibitory Ser9 residue. Our results point to alterations in phosphorylation and/or dephosphorylation homeostasis as key mechanisms underlying the deficits in LTD and hippocampus-dependent learning found in THY-Tau22 mice. Ó 2015 Elsevier Inc. All rights reserved. 1. Introduction It is well known that aging and the progression of neurode- generative diseases like Alzheimer’s disease (AD) are characterized by the deterioration of cognitive functions, in particular of declar- ative forms of memory (Di et al., 2007; Glodzik et al., 2011; Hornberger and Piguet, 2012; McKhann et al., 1984; Nestor et al., 2006; Sydow et al., 2011; Van der Jeugd et al., 2011, 2012). Less known is that in most AD patients and some AD mouse models, the decline in cognition is accompanied by neuropsychiatric symptoms at some stage of the disease (Alexander et al., 2011; Lyketsos et al., 2011; Price et al., 2012; Van Der Jeugd et al., 2013). Since cognitive decline and psychiatric symptoms are due to dysfunctions of synaptic processes (Hoover et al., 2010; Moechars et al., 1999; Rowan et al., 2003; Ting et al., 2007; Van Spronsen and Hoogenraad, 2010), it is tempting to use readouts of synaptic function as early markers for the onset of AD pathology. It is widely believed that synaptic function bidirectionally adapts to the recent history of activation by plastic changes in synaptic transmission. A robust sustained increase in synaptic transmission is referred to as long-term potentiation (LTP) and a lasting decrease is referred to as long-term depression (LTD). Both LTP and LTD are considered as models for memory storage at the cellular level and can be artificially induced by certain protocols of electrical stimu- lation (see Bliss and Collingridge, 1993; Citri and Malenka, 2008; Collingridge et al., 2010 for further details). Over the past decade, LTP has developed into a prime tool for the detection of synaptic deficits in AD mouse models. This is because it has been proven to be a sensitive indicator for early-onset pathology, and its mechanisms are well explored which facilitates causal conclusions (Hoover et al., 2010; Moechars et al., 1999; Rowan * Corresponding authors at: Laboratory of Biological Psychology, University of Leuven, KU Leuven, Tiensestraat 102, box 3714, B-3000 Leuven, Belgium. Tel.: þ3216325816; fax: þ3216326099. E-mail address: Detlef.Balschun@ppw.kuleuven.be (D. Balschun). Contents lists available at ScienceDirect Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging 0197-4580/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2014.09.015 Neurobiology of Aging 36 (2015) 730e739