What are chemokine receptors and ligands doing in the brain? There are 40–50 chemokine ligands, small secreted proteins of 60–100 amino acids. About 20 chemokine receptors exist, ordered in distinct families and coupled to G-proteins. One might think these signalling molecules, which act to attract migrating cells, have a uniquely pathological role in neurodegenerative diseases or to mediate inflammatory responses. Their functions however, seem likely to be wider than that (Rostene et al. 2007; Guyon et al. 2008). Certainly, chemokine signalling contributes to inflammatory responses by attracting cells of the immune system to regions of infection or damage in the brain. But chemokines are also involved in other processes involving cell motility including the control of neuronal migration during brain development (Tiveron & Cremer, 2008) and also the recruitment of endothelial progenitor cells to form blood vessels during cerebral angiogenesis. Chemokine ligands are liberated by microglia, by astrocytes and also by some neurones. The ligand CXCL12, for instance, is present in synaptic vesicles of granule cells of the hippocampal dentate gyrus. Both glial and neuronal cells express G-protein coupled, cytokine receptors. Often they are expressed selectively in distinct brain areas by specific types of neurones, sometimes with a distinct developmental profile. For instance, adult dopaminergic cells of the substantia nigra express the cytokine receptor CCR2, while cortical Cajal-Retzius cells, which largely disappear during development, express the CXCR4 receptor. But what are they doing in the brain? One way to find out is to study the physiology of cells that express chemokine receptors. Such work has been greatly facilitated by the development of BAC transgenic animals in which fluorescent reporter proteins reflect the expression of specific receptor molecules. In a recent report in The Journal of Physiology, Marchionni and colleagues (2010) describe work on a CXCR4-EGFP animal. This chemokine receptor binds a specific chemokine ligand, CXCL12, also known as the stromal-cell derived factor 1. The CXCR4 receptor is expressed by progenitor cells in the dentate gyrus of post-natal hippocampus (Bhattacharyya et al. 2008). Marchionni et al. now show that Cajal-Retzius cells in the CA1 region of the hippocampus also express the receptor. Cajal-Retzius cells secrete the large glycoprotein reelin, which has a crucial role in the migration of cortical neurones. In the neocortex, they seem to be largely transient, disappearing or at least stopping reelin secretion, when migration is complete. In the CA1 region of the hippocampus however, Marchionni and colleagues show that the Cajal-Retzius cells remain at least until P16–P24 when their experiments were performed. The somata of fluorescent cells in CXCR4-EGFP animals were found in the stratum lacunosum-moleculare of the CA1 region, so they are not pyramidal cells. They express reelin as expected, but also the Ca2+-binding protein calretinin, a marker of subsets of cortical interneurones. Are these chemokine receptor-expressing cells interneurones, then? Electrophysiological and anatomical arguments suggest probably not. Marchionni et al. show their electrical properties differ markedly from typical GABAergic interneurons of the same layer. Furthermore, electron microscopy revealed that axons of these Cajal-Retzius cells form terminals which, while containing transmitter vesicles, do not face classical postsynaptic specializations. And yet, both these points could be otherwise explained, so conclusive proof of the identity of released transmitter awaits a simultaneous record from a postsynaptic cell. If the output of the reelin and CXCR4-expressing fluorescent cells is not completely resolved, they are clearly integrated into synaptic circuits of the CA1 region. They receive sparse GABAergic synaptic events, which can trigger action potentials, due presumably to high levels of internal chloride. However, they express few, if any, glutamatergic receptors. These cells should of course respond to the CXRC4 ligand, stromal-cell derived factor 1 or CXCL12. And they do. It generates a slow probably K+ current mediated hyperpolarization. So Marchionni and colleagues have set the stage to ask in a much more informed way the question: what is this chemokine signalling system doing? CXRC4 receptors are expressed by adult Cajal-Retzius cells integrated into circuits in the CA1 region of the hippocampus. Probably, at P12–P24 in the CA1 region, they are not participating in migration. Possibly, they reflect a strategic signalling reserve that could be rapidly expanded when inflammatory processes are engaged. More probably, perhaps they participate in signalling in the adult CA1 region. The article shows that activation of CXRC4 receptors by their ligand CXCL12 abolishes the spontaneous discharges of these Cajal-Retzius cells. So chemokine signalling should abolish release of molecules contained in the vesicles of Cajal-Retzius cell axons. The absence of classical postsynaptic structures and the presence in the stratum lacunosum-moleculare of CA1 points to effects by volume transmission on afferents terminating in this layer. It is intriguing to wonder whether that volume transmission is mediated by GABA, or glutamate or even reelin. Whichever it is, this article seems likely to modify once again our vision of hippocampal circuit function.
Read full abstract
May 1, 2016
Seung Min Park + 13
Open Access