Regular articlePGE2-EP3 signaling pathway impairs hippocampal presynaptic long-term plasticity in a mouse model of Alzheimer's disease
Introduction
Alzheimer's disease (AD) is a progressive and devastating neurodegenerative disease characterized by deficits in learning and memory processes. There is considerable evidence that neuroinflammation involving the activation of glial cells contributes to the disease progression and pathology (Akiyama et al., 2000, Heneka and O'Banion, 2007). As such, epidemiological studies have revealed that chronic intake of nonsteroidal anti-inflammatory drugs (NSAIDs) reduced the prevalence of AD (McGeer and McGeer, 2007). Furthermore, clinical trials have revealed that NSAIDs, when given to asymptomatic patients, reduce AD incidence, whereas they have adverse effect on AD pathogenesis in its later stages (Breitner et al., 2011).
When activated in neuroinflammatory conditions, glia release a plethora of neuroinflammatory molecules such as inflammatory cytokines, chemokines, and prostanoids (Eikelenboom et al., 1994). The prostanoid prostaglandin E2 (PGE2) plays pivotal functions in inflammation (Bos et al., 2004). PGE2 is produced from arachidonic acid by the microsomal prostaglandin-E2 synthase (mPGES) and by 2 rate-limiting enzymes, Cox-1 and Cox-2 (Smith et al., 1991), which are expressed by hippocampal neurons (Yasojima et al., 1999), astrocytes and microglia (Font-Nieves et al., 2012). Although Cox-1 is constitutively expressed, Cox-2 and mPGES are strongly activated by and during neuroinflammation (Font-Nieves et al., 2012). PGE2 can bind to 4 different subtypes of G-protein–coupled receptors (EP1–4), which regulate adenylyl cyclase (AC) activity and/or phosphoinositol turnover and intracellular calcium mobilization (Breyer et al., 2001).
PGE2 plays an important role in the pathophysiology of AD. It is a primary target of NSAIDs, and its level is elevated together with the expression of Cox-2 in the brain of AD patients (Kitamura et al., 1999, Montine et al., 1999, Yasojima et al., 1999). Both in vitro and in vivo, PGE2 stimulates amyloid beta (Aß) production by microglial cells, astrocytes, and neurons (Hoshino et al., 2007). Selective inhibition of Cox-2 by NS398 acutely prevents the Aß-induced impairment of long-term potentiation (LTP) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors–mediated synaptic transmission at CA3–CA1 synapses (Kotilinek et al., 2008). Exogenous addition of PGE2 did not impair by itself LTP in wild-type mice but prevented the ability of NS398 to restore LTP impairment induced by synthetic Aß suggesting complex interactions between PGE2, Aβ, and postsynaptic forms of LTP (Kotilinek et al., 2008).
AD, at least in its early stage, is thought to involve synaptic dysfunction and loss (Jacobsen et al., 2006, Selkoe, 2002, Sheng et al., 2012). Connections between the dentate gyrus (DG) and the hippocampal CA3 region through mossy fiber (Mf) synapses have been proposed to participate in the rapid encoding of novel memory (Kesner, 2007), a mnemonic process particularly affected in AD conditions. Mf synapses onto CA3 pyramidal cells display a wide dynamic range of presynaptic plasticity, including prominent short-term plasticity and a form of LTP that is independent of N-methyl-D-aspartate (NMDA) receptors (Henze et al., 2002, Salin et al., 1996). Alterations in Mf synaptic function in the context of AD have only been studied in senescent (24- to 25-month old) Tg2576 mice that is long after a massive load of amyloid plaques (Witton et al., 2010).
Here we thus studied Mf-CA3 synaptic function in the APPswe/PS1ΔE9 (APP/PS1) mouse model of AD in relation with PGE2. APP/PS1 mice are characterized by an over-production of Aß protein leading to a noticeable load of amyloid plaques around 12 months of age (Jankowsky et al., 2004) and display synaptic dysfunction (Volianskis et al., 2010) and learning deficits (Lagadec et al., 2012, Reiserer et al., 2007). We report that acute application of PGE2 impairs presynaptic Mf-LTP in young mice through activation of EP3 receptors. In APP/PS1 mice, presynaptic Mf-LTP was noticeably impaired at 12 months of age in parallel with a building up of endogeneous levels of PGE2 in the hippocampus. Mf-LTP could be fully rescued by blockade of EP3 receptors. Considering the diverse physiological roles of PGE2, directly targeting the EP3 receptor may prove to be a more specific therapeutical strategy in AD than the global inhibition of prostaglandins by NSAIDs.
Section snippets
Ethical approval
Animal anesthesia and euthanasia procedures were carried out in accordance with the Animal Protection Association of ethical standards and the French legislation concerning animal experimentation and were approved by the University of Bordeaux/CNRS Animal Care and Use Committee (#55).
Animals
The animals used in this study were male APP/PS1 mice obtained from Jackson Laboratory (Bar Harbor, ME, USA) and their wild-type (WT) littermates (C57BL6/J). The APP/PS1 mice express a chimeric mouse/human amyloid
PGE2 impairs presynaptic long-term potentiation at Mf–CA3 synapses
We tested the effects of PGE2 on Mf-EPSCs recorded from CA3 pyramidal cells of P19–P21 wild-type mice using the whole-cell voltage clamp mode of the patch clamp technique (Fig. 1A). Mf-EPSCs evoked by minimal intensity stimulation at low frequency (0.1 Hz) were not affected by bath application of 1–10 μM PGE2 (Fig. 1B). Mf-CA3 synapses display prominent forms of presynaptic short-term plasticity (Nicoll and Schmitz, 2005), including paired-pulse facilitation (PPF: 2 stimulations separated by
Discussion
Our findings demonstrate that PGE2, acting through the EP3 receptor subtype, inhibits presynaptic long-term plasticity at Mf-CA3 synapses. We further provide evidence that in the APP/PS1 mouse model of AD, the PGE2-EP3 receptor signaling pathway is responsible for the impairment of presynaptic LTP at Mf-CA3 synapses by showing that the blockade of EP3 receptors fully rescues the LTP at 12-month-old, an age characterized by a neuroinflammatory reaction and chronically elevated levels of the
Disclosure statement
The authors have no conflicts of interest to disclose.
Acknowledgements
The authors thank Sílvia Viana da Silva for help with electrophysiological recordings and fruitful discussions and Noelle Grosjean for genotyping APPswe/PS1ΔE9 mice. The authors thank Ashley L. Kees for careful reading of the manuscript and Benoit Silvestre de Ferron for the cartoon shown in Fig. 1A. The authors also thank Marlène Maitre (Microdissection Laser plateform, Neurocentre Magendie, Inserm U862), Thierry Lesté-Lasserre (Genotyping plateform, Neurocentre Magendie, Inserm U862) for
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