Please cite this article in press as: Dewachter, I. et al., Modulation of synaptic plasticity and Tau phosphorylation by wild-type and mutant presenilin1, Neurobiol Aging (2007), doi:10.1016/j.neurobiolaging.2006.11.019 ARTICLE IN PRESS NBA-6708; No. of Pages 14 Neurobiology of Aging xxx (2007) xxx–xxx Modulation of synaptic plasticity and Tau phosphorylation by wild-type and mutant presenilin1 I. Dewachter a , L. Ris b , S. Croes a , P. Borghgraef a , H. Devijver a , T. Voets c , B. Nilius c , E. Godaux b , F. Van Leuven a,∗ a Experimental Genetics Group, K.U.Leuven, 3000 Leuven, Belgium b Laboratory of Neurosciences, University of Mons-Hainaut, 7000 Mons, Belgium c Laboratory of Physiology, K.U.Leuven, 3000 Leuven, Belgium Received 7 August 2006; received in revised form 9 November 2006; accepted 25 November 2006 Abstract The function of presenilin1 (PS1) in intra-membrane proteolysis is undisputed, as is its role in neurodegeneration in FAD, in contrast to its exact function in normal conditions. In this study, we analyzed synaptic plasticity and its underlying mechanisms biochemically in brain of mice with a neuron-specific deficiency in PS1 (PS1(n-/-)) and compared them to mice that expressed human mutant PS1[A246E] or wild-type PS1. PS1(n-/-) mice displayed a subtle impairment in Schaffer collateral hippocampal long-term potentiation (LTP) as opposed to normal LTP in wild-type PS1 mice, and a facilitated LTP in mutant PS1[A246E] mice. This finding correlated with, respectively, increased and reduced NMDA receptor responses in PS1[A246E] mice and PS1(n-/-) mice in hippocampal slices. Postsynaptically, levels of NR1/NR2B NMDA-receptor subunits and activated -CaMKII were reduced in PS1(n-/-) mice, while increased in PS1[A246E] mice. In addition, PS1(n-/-) mice, displayed reduced paired pulse facilitation, increased synaptic fatigue and lower number of total and docked synaptic vesicles, implying a presynaptic function for wild-type presenilin1, unaffected by the mutation in PS1[A246E] mice. In contrast to the deficiency in PS1, mutant PS1 activated GSK-3 by decreasing phosphorylation on Ser-9, which correlated with increased phosphorylation of protein tau at Ser-396–Ser-404 (PHF1/AD2 epitope). The synaptic functions of PS1, exerted on presynaptic vesicles and on postsynaptic NMDA-receptor activity, were concluded to be independent of alterations in GSK-3 activity and phosphorylation of protein tau. © 2006 Elsevier Inc. All rights reserved. Keywords: Presenilin; FAD mutation; Synaptic plasticity; NMDA receptor; Synaptic vesicles; Presynaptic; Postsynaptic; Tau 1. Introduction Many questions regarding the functions exerted by presenilins (PS), PS1 and PS2, either directly or indirectly in synaptic plasticity, affecting both structural and functional characteristics, remain to be explored to the fullest. The essential role of PS1 in -secretase activity (De Strooper et al., 1998) is undisputed, as the essential active-site compo- nent of the -secretase complex containing further nicastrin, aph-1 and pen-2 (Iwatsubo, 2004; Kopan and Ilagan, 2004; ∗ Corresponding author at: Experimental Genetics Group (LEGT EGG), K.U.Leuven, Campus Gasthuisberg, ON1-06.602, 3000 Leuven, Belgium. Tel.: +32 16 34 58 88; fax: +32 16 34 58 71. E-mail address: fredvl@med.kuleuven.be (F. Van Leuven). Steiner, 2004; Thinakaran and Parent, 2004). The direct involvement of PS1 in very diverse (patho)physiological processes either as -secretase with a tantalizing number of substrates, or as mediator of protein trafficking and calcium homeostasis (Herms et al., 2003; Leissring et al., 2000; Ris et al., 2003; Yoo et al., 2000) needs to be further explored. In this respect, we have been offered an experiment of nature that is as interesting as it is tragic: the familial forms of Alzheimer’s disease (AD) that are caused by the many mutations in PS1 are the most early and aggressive in onset and course (Hutton and Hardy, 1997; Schellenberg et al., 2000). Many, if not all of the actions of PS1 were indeed brought to light by studies of the role of mutant PS1 in the pathology in EOFAD, followed by studies of PS1 deficient mice and cells. In addition EOFAD linked to PS1 mutations 0197-4580/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2006.11.019