Acute Pannexin 1 Blockade Mitigates Early Synaptic Plasticity Defects in a Mouse Model of Alzheimer's Disease.

Carolina Flores-Muñoz,Claudio Hetz,Pablo Muñoz,Arlek M Gonzalez-Jamett,Álvaro O Ardiles,Elena Mery,Ivana Gajardo,Claudio Córdova,Claudia Durán-Aniotz,Bárbara Gómez,Paula Mujica,Daniela Lopez-Espíndola

doi:10.3389/fncel.2020.00046

Abstract

Synaptic loss induced by soluble oligomeric forms of the amyloid β peptide (sAβos) is one of the earliest events in Alzheimer’s disease (AD) and is thought to be the major cause of the cognitive deficits. These abnormalities rely on defects in synaptic plasticity, a series of events manifested as activity-dependent modifications in synaptic structure and function. It has been reported that pannexin 1 (Panx1), a nonselective channel implicated in cell communication and intracellular signaling, modulates the induction of excitatory synaptic plasticity under physiological contexts and contributes to neuronal death under inflammatory conditions. Here, we decided to study the involvement of Panx1 in functional and structural defects observed in excitatory synapses of the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (Tg) mice, an animal model of AD. We found an age-dependent increase in the Panx1 expression that correlates with increased Aβ levels in hippocampal tissue from Tg mice. Congruently, we also observed an exacerbated Panx1 activity upon basal conditions and in response to glutamate receptor activation. The acute inhibition of Panx1 activity with the drug probenecid (PBN) did not change neurodegenerative parameters such as amyloid deposition or astrogliosis, but it significantly reduced excitatory synaptic defects in the AD model by normalizing long-term potentiation (LTP) and depression and improving dendritic arborization and spine density in hippocampal neurons of the Tg mice. These results suggest a major contribution of Panx1 in the early mechanisms leading to the synaptopathy in AD. Indeed, PBN induced a reduction in the activation of p38 mitogen-activated protein kinase (MAPK), a kinase widely implicated in the early neurotoxic signaling in AD. Our data strongly suggest that an enhanced expression and activation of Panx1 channels contribute to the Aβ-induced cascades leading to synaptic dysfunction in AD.

Highlights

Alzheimer’s disease (AD) is an age-dependent neurodegenerative disorder characterized by severe deterioration of cognitive functions leading to dementia (Selkoe, 2001)
In order to evaluate whether this augmented pannexin 1 (Panx1) expression associated with an enhanced Panx1 activity, we performed dye uptake experiments in hippocampal slices from Wt and type (Wt) or APPswe/PSEN1∆E9 mice (Tg mice) using ethidium bromide (EtBr) in the presence of La+3 to block the uptake through connexin hemichannels (Orellana et al, 2011b)
We show that Panx1, a nonselective transmembrane channel that connects intracellular and extracellular spaces (MacVicar and Thompson, 2010), is implicated in the sAβos-induced early synaptic dysfunction observed in a mouse model of AD

Summary

Introduction

Alzheimer’s disease (AD) is an age-dependent neurodegenerative disorder characterized by severe deterioration of cognitive functions leading to dementia (Selkoe, 2001). Synaptic dysfunction and memory impairments have been reported in several animal models of AD before the appearance of neuropathological changes (Duyckaerts et al, 2008; Götz and Ittner, 2008; Philipson et al, 2010) In this regard, a number of evidences suggest that soluble oligomeric forms of Aβ (sAβos), identified in AD patients (Gong et al, 2003; Fukumoto et al, 2010) and AD animal models (Mucke et al, 2000; Price et al, 2014), precede the fibrillar amyloid deposition and tau pathology and have been implicated in the synaptopathy observed before the neurodegeneration appearance (Selkoe, 2008; Sheng et al, 2012). SAβos from different sources (i.e., synthetic, cell line-derived, human and mouse brain-derived) induce detrimental effects on memory (Cleary et al, 2005; Reed et al, 2011), synaptic morphology (Hsieh et al, 2006; Lacor et al, 2007; Shankar, 2007; Price et al, 2014) and glutamate receptor trafficking, expression and function (Snyder et al, 2005; Hsieh et al, 2006; Shankar, 2007; Miñano-Molina et al, 2011; Ardiles et al, 2012), and impair excitatory synaptic plasticity (Kim et al, 2001; Townsend et al, 2006; Klyubin et al, 2008; Shankar et al, 2008; Li et al, 2009)

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