The immune system (IS) and the central nervous system (CNS) are functionally coupled and a large number of endogenous molecules (i.e. the chemokines for the IS and the classic neurotransmitters for the CNS) are shared in common between the two systems. These interactions are key elements for the elucidation of the pathogenesis of central inflammatory diseases. In recent years evidence have been provided supporting the role of chemokines as modulators of central neurotransmission. It is the case of the chemokines CCL2 and CXCL12 that control pre and / or postsynaptically the chemical transmission. This article aims to review the functional cross-talk linking another endogenous proinflammatory factor released by glial cells, i.e. the chemokine Regulated upon Activation Normal T cell Expressed and Secreted, (RANTES, CCL5) and the principal neurotransmitter in CNS (i.e. glutamate) in physiological and pathological conditions. In particular, the review will discuss preclinical data concerning the role of CCL5 as a modulator of central glutamatergic transmission in healthy and demyelinating disorders. The CCL5-mediated control of glutamate release at chemical synapses could be relevant either to the onset of psychiatric symptoms that often accompany the development of MS, but also it might indirectly give a rationale for the progression of inflammation and demyelination. The impact of disease modifying therapies for the cure of MS on the endogenous availability of CCL5 in CNS will be also summarized. We apologize in advance for omission in our coverage of the existing literature.

The effects of the recombinant chemokine human RANTES (hRANTES) on the release of glutamate from human neocortex glutamatergic nerve endings were investigated. hRANTES facilitated the spontaneous release of d [³H]d-aspartate ([³H]dASP-) by binding Pertussis toxin-sensitive G-protein-coupled receptors (GPCRs), whose activation caused Ca²⁺mobilization from inositol trisphosphate-sensitive stores and cytosolic tyrosine kinase-mediated phosphorylations. Facilitation of release switched to inhibition when the effects of hRANTES on the 12 mmK⁺-evoked [³H]d-ASP exocytosis were studied. Inhibition of exocytosis relied on activation of Pertussis toxin-sensitive GPCRs negatively coupled to adenylyl cyclase. Both hRANTES effects were prevented by met-RANTES, an antagonist at the chemokine receptors (CCRs) of the CCR1, CCR3, and CCR5 subtypes. Interestingly, human neocortex glutamatergic nerve endings seem to possess all three receptor subtypes. Blockade of CCR1 and CCR5 by antibodies against the extracellular domain of CCRs prevented both the hRANTES effect on [³H]d-ASP release, whereas blockade of CCR3 prevented inhibition, but not facilitation, of release. The effects of RANTES on the spontaneous and the evoked release of [³H]d-ASP were also observed in experiments with mouse cortical synaptosomes, which may therefore represent an appropriate animal model to study RANTES-induced effects on neurotransmission. It is concluded that glutamate transmission can be modulated in opposite directions by RANTES acting at distinct CCR receptor subtypes coupled to different transduction pathways, consistent with the multiple and sometimes contrasting effects of the chemokine.

J. Neurochem. (2011) 117, 516–527. Abstract Rat hippocampal glutamatergic terminals possess NMDA autoreceptors whose activation by low micromolar NMDA elicits glutamate exocytosis in the presence of physiological Mg²⁺ (1.2 mM), the release of glutamate being significantly reduced when compared to that in Mg²⁺-free condition. Both glutamate and glycine were required to evoke glutamate exocytosis in 1.2 mM Mg²⁺, while dizocilpine, cis-4-[phosphomethyl]-piperidine-2-carboxylic acid and 7-Cl-kynurenic acid prevented it, indicating that occupation of both agonist sites is needed for receptor activation. d-serine mimicked glycine but also inhibited the NMDA/glycine-induced release of [³H]d-aspartate, thus behaving as a partial agonist. The NMDA/glycine-induced release in 1.2 mM Mg²⁺ strictly depended on glycine uptake through the glycine transporter type 1 (GlyT1), because the GlyT1 blocker N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl])sarcosine hydrochloride, but not the GlyT2 blocker Org 25534, prevented it. Accordingly, [³H]glycine was taken up during superfusion, while lowering the external concentration of Na⁺, the monovalent cation co-transported with glycine by GlyT1, abrogated the NMDA-induced effect. Western blot analysis of subsynaptic fractions confirms that GlyT1 and NMDA autoreceptors co-localize at the pre-synaptic level, where GluN3A subunits immunoreactivity was also recovered. It is proposed that GlyT1s coexist with NMDA autoreceptors on rat hippocampal glutamatergic terminals and that glycine taken up by GlyT1 may permit physiological activation of NMDA pre-synaptic autoreceptors.

J. Neurochem. (2012) 121, 428–437. The impact of Regulated upon Activation Normal T cells Expressed and Secreted (RANTES) on the release of pre‐loaded [³H]d‐aspartate ([³H]d‐ASP) from mouse spinal cord synaptosomes was investigated. RANTES (0.01–1 nM) failed to affect the spontaneous release, but facilitated the 15 mM K⁺‐evoked overflow of [³H]d‐ASP. Incubation of synaptosomes with antibodies raised against the chemokine receptor (CCR)1 and CCR5 proteins prevented RANTES‐induced facilitation of glutamate exocytosis, whereas anti‐CCR3 antibody was inefficacious. Accordingly, BX513 and d‐Ala‐peptide T‐amide (DAPTA) CCR1 and CCR5 antagonists, respectively, prevented RANTES‐induced effect, whereas the CCR3 antagonist SB 328437 was inactive. To compare these findings to previous results, we quantified the effects of CCR antagonists on the RANTES‐induced modifications of the spontaneous and the K⁺‐evoked [³H]d‐ASP release in the mouse cortex. Here, CCR1 and CCR5, but not CCR3, antagonists prevented the RANTES‐mediated [³H]d‐ASP release, whereas RANTES‐induced inhibition of the 12 mM K⁺‐evoked [³H]d‐ASP exocytosis was also antagonized by SB 328437. Facilitation of glutamate exocytosis in spinal cord relied on PLC‐dependent mobilization of Ca²⁺ from IP₃‐sensitive stores; adenylyl cyclase was not involved. CCR1, CCR3 and CCR5 receptor proteins were present in spinal cord synaptosomal and gliosomal lysates, although RANTES‐induced changes to glutamate release could not be observed in gliosomes. Our results confirm the role of RANTES as modulator of glutamate transmission.