Fractalkine (CX3CL1) enhances hippocampal N-methyl-d-aspartate receptor (NMDAR) function via d-serine and adenosine receptor type A2 (A2AR) activity

Abstract

BackgroundN-Methyl-d-aspartate receptors (NMDARs) play fundamental roles in basic brain functions such as excitatory neurotransmission and learning and memory processes. Their function is largely regulated by factors released by glial cells, including the coagonist d-serine. We investigated whether the activation of microglial CX3CR1 induces the release of factors that modulate NMDAR functions.MethodsWe recorded the NMDAR component of the field excitatory postsynaptic potentials (NMDA-fEPSPs) elicited in the CA1 stratum radiatum of mouse hippocampal slices by Shaffer collateral stimulation and evaluated d-serine content in the extracellular medium of glial primary cultures by mass spectrometry analysis.ResultsWe demonstrated that CX3CL1 increases NMDA-fEPSPs by a mechanism involving the activity of the adenosine receptor type A2 (A2AR) and the release of the NMDAR coagonist d-serine. Specifically (1) the selective A2AR blocker 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH58261) and the genetic ablation of A2AR prevent CX3CL1 action while the A2AR agonist 5-(6-amino-2-(phenethylthio)-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydrofuran-2-carboxamide (VT7) mimics CX3CL1 effect, and (2) the selective blocking of the NMDAR glycine (and d-serine) site by 5,7-dicholorokynurenic acid (DCKA), the enzymatic degradation of d-serine by d-amino acid oxidase (DAAO) and the saturation of the coagonist site by d-serine, all block the CX3CL1 effect. In addition, mass spectrometry analysis demonstrates that stimulation of microglia and astrocytes with CX3CL1 or VT7 increases d-serine release in the extracellular medium.ConclusionsCX3CL1 transiently potentiates NMDAR function though mechanisms involving A2AR activity and the release of d-serine.

Role of fractalkine–CX3CR1 pathway in seizure-induced microglial activation, neurodegeneration, and neuroblast production in the adult rat brain

“…In an attempt to further evaluate the neuroprotective effect of inhibiting the CX3CR1 pathway, we studied the expression of excitatory and inhibitory synaptic scaffolding proteins, PSD-95 and gephyrin, which may suggest an imbalance in neuronal excitability as a contributor to neurodegeneration. PSD-95 and gephyrin are known to modulate excitatory and inhibitory synaptic transmission (Beique and Andrade, 2003;Prange et al, 2004;Varley et al, 2011) and the fractalkine-CX3CR1 pathway has been shown to regulate both glutamatergic excitatory and GABAergic inhibitory synaptic transmission (Lauro et al, 2008;Lauro et al, 2010;Piccinin et al, 2010;Scianni et al, 2013). In addition, in cortical brain tissues from TLE patients, modulating this pathway by adding recombinant fractalkine, decreased GABA current reduction on repeated GABA application, though, the recovery of currents to basal values was also affected, suggesting a possible desensitization of GABA receptors (Roseti et al, 2013).…”

“…Various inflammatory mediators which are known to regulate microglial activation (Cardona et al, 2006;D'Haese et al, 2012), have also been implicated in adult neurogenesis and synaptic transmission (Butovsky et al, 2006;Lauro et al, 2010;Scianni et al, 2013). Fractalkine is an inflammatory chemokine secreted by neurons and astrocytes.…”

Beyond neurovascular coupling, role of astrocytes in the regulation of vascular tone

“…Microglia utilizes targeted phagocytosis for synapse organization during development and for re-organization after injury (Stevens et al, 2007, Wake et al, 2009, Tremblay et al, 2010). Microglia also modulate neuronal activity via small molecular messengers such as ATP, BDNF and CX3CL1 (Coull et al, 2005, Hayashi et al, 2006, Scianni et al, 2013, Siskova and Tremblay, 2013) thus placing microglia in the midst of an expanded paradigm—the “quad-partite” synapse (Schafer et al, 2013). In addition, microglia depend on continuous microglial-neuronal crosstalk which is mediated by neuronal ligand-microglia receptor interactions such as CX3CL1/CX3CR1, CD47/CD177, and CD22/CD45 to maintain their surveillance activities; the absence of this communication constitutes an initial “signal” to escalate/alter microglial function (Hanisch and Kettenmann, 2007, Saijo and Glass, 2011).…”

The Effect of PSD-93 Deficiency on the Expression of Early Inflammatory Cytokines Induced by Ischemic Brain Injury

“…The release of proinflammatory cytokines can in turn increase the neuronal damage, thus creating a vicious cycle in the course of ischemic brain injury. On the other hand, through specific chemokines and their receptors, such as CD22/CD45, CD47/ CD172a, CD200/CD200R, and CX3CL1/CX3CR1, neurons and microglia can activate a series of signaling pathways and ultimately regulate neuronal apoptosis [19][20][21].…”