Platelet Activating Factor Enhances Synaptic Vesicle Exocytosis Via PKC, Elevated Intracellular Calcium, and Modulation of Synapsin 1 Dynamics and Phosphorylation.

Jennetta W Hammond,Harris A Gelbard,Shao-Ming Lu

doi:10.3389/fncel.2015.00505

Jennetta W Hammond, Harris A Gelbard + Show 1 more

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https://doi.org/10.3389/fncel.2015.00505

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Journal: Frontiers in cellular neuroscience	Publication Date: Jan 8, 2016
Citations: 15	License type: cc-by

Affiliation: University of Rochester

Abstract

Platelet activating factor (PAF) is an inflammatory phospholipid signaling molecule implicated in synaptic plasticity, learning and memory and neurotoxicity during neuroinflammation. However, little is known about the intracellular mechanisms mediating PAF’s physiological or pathological effects on synaptic facilitation. We show here that PAF receptors are localized at the synapse. Using fluorescent reporters of presynaptic activity we show that a non-hydrolysable analog of PAF (cPAF) enhances synaptic vesicle release from individual presynaptic boutons by increasing the size or release of the readily releasable pool and the exocytosis rate of the total recycling pool. cPAF also activates previously silent boutons resulting in vesicle release from a larger number of terminals. The underlying mechanism involves elevated calcium within presynaptic boutons and protein kinase C activation. Furthermore, cPAF increases synapsin I phosphorylation at sites 1 and 3, and increases dispersion of synapsin I from the presynaptic compartment during stimulation, freeing synaptic vesicles for subsequent release. These findings provide a conceptual framework for how PAF, regardless of its cellular origin, can modulate synapses during normal and pathologic synaptic activity.

Highlights

Platelet activating factor (PAF) is an inflammatory phospholipid signaling molecule implicated in synaptic plasticity, learning and memory, and neurotoxicity (Clark et al, 1992; Wieraszko et al, 1993; Gelbard et al, 1994; Izquierdo et al, 1995; Teather et al, 1998; Xu et al, 2004)
We show that PAF increases presynaptic vesicle exocytosis through protein kinase C (PKC) activation and elevated intracellular calcium within presynaptic boutons
As synapsin I dispersion is calcium sensitive and regulated by phosphorylation of synapsin I (Chi et al, 2001, 2003; Cesca et al, 2010), we examined whether cPAF altered the levels of synapsin I phosphorylation at two sites known to be important for synapsin I binding to synaptic vesicles (Site1-ser9 and Site 3-Ser 603)

Summary

Introduction

Platelet activating factor (PAF) is an inflammatory phospholipid signaling molecule implicated in synaptic plasticity, learning and memory, and neurotoxicity (Clark et al, 1992; Wieraszko et al, 1993; Gelbard et al, 1994; Izquierdo et al, 1995; Teather et al, 1998; Xu et al, 2004). Pharmacological or genetic inhibition of the PAF receptor (PAFR) in rodent models of neuroinflammatory disease successfully decreases neurological damage and inflammation (Kihara et al, 2005; Farooqui et al, 2006; Belayev et al, 2008; Eggert et al, 2009; Musto and Samii, 2011; Rodrigues et al, 2011; Okubo et al, 2012; Motoyama et al, 2013) These studies validate the PAF/PAFR associated signal cascade as viable targets for reducing inflammatory damage to the CNS and warrant further study into the mechanisms of how an overabundance in PAF signaling contributes to synaptic damage and the continuing harmful cycle of neuroinflammation

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