The chemokine CXCL12 and the HIV‐1 envelope protein gp120 regulate spontaneous activity of Cajal–Retzius cells in opposite directions

Key points•  The CXC chemokine ligand 12 (CXCL12) modulates spontaneous firing of Cajal–Retzius cells via the CXC chemokine receptor 4 (CXCR4). However, the underlying mechanism(s) are poorly understood. CXCR4 also binds the human immunodeficiency virus type 1 (HIV‐1) envelope glycoprotein 120 (gp120), but the functional effects of this interaction on Cajal–Retzius cell excitability remain unknown. •  We show that CXCL12 reduces spontaneous firing in Cajal–Retzius cells by opening a BK‐type calcium‐activated potassium conductance, whereas gp120 increases their excitability via a calcium‐ and chloride‐dependent mechanism. •  Our data suggest that, depending on the use of CXCL12 or gp120 as ligands, partial agonism at the CXCR4 receptor generates calcium responses of different strengths, which lead to the recruitment of either calcium‐activated potassium or chloride channels. •  We propose that HIV infection disrupts a signalling pathway important for the regulation of the excitability of Cajal–Retzius cells, and alters their functions.Abstract  Activation of the CXC chemokine receptor 4 (CXCR4) in Cajal–Retzius cells by CXC chemokine ligand 12 (CXCL12) is important for controlling their excitability. CXCR4 is also a co‐receptor for the glycoprotein 120 (gp120) of the envelope of the human immunodeficiency virus type 1 (HIV‐1), and binding of gp120 to CXCR4 may produce pathological effects. In order to study CXCR4‐dependent modulation of membrane excitability, we recorded in cell‐attached configuration spontaneous action currents from hippocampal stratum lacunosum‐moleculare Cajal–Retzius cells of the CXCR4‐EGFP mouse. CXCL12 (50 n m ) powerfully inhibited firing independently of synaptic transmission, suggesting that CXCR4 regulates an intrinsic conductance. This effect was prevented by conditioning slices with BAPTA‐AM (200 μ m ), and by blockers of the BK calcium‐dependent potassium channels (TEA (1 m m) , paxilline (10 μ m) and iberiotoxin (100 n m) ). In contrast, exposure to gp120 (pico‐ to nanomolar range, alone or in combination with soluble cluster of differentiation 4 (CD4)), enhanced spontaneous firing frequency. This effect was prevented by the CXCR4 antagonist AMD3100 (1 μ m ) and was absent in EGFP‐negative stratum lacunosum‐moleculare interneurons. Increased excitability was prevented by treating slices with BAPTA‐AM or bumetanide, suggesting that gp120 activates a mechanism that is both calcium‐ and chloride‐dependent. In conclusion, our results demonstrate that CXCL12 and gp120 modulate the excitability of Cajal–Retzius cells in opposite directions. We propose that CXCL12 and gp120 either generate calcium responses of different strength or activate distinct pools of intracellular calcium, leading to agonist‐specific responses, mediated by BK channels in the case of CXCL12, and by a chloride‐dependent mechanism in the case of gp120.