Stromal cell-derived factor-1alpha modulation of the excitability of rat substantia nigra dopaminergic neurones: presynaptic mechanisms.
In rat substantia nigra (SN), Chemokine (CXC motif) receptor 4 (CXCR4) for the chemokine stromal cell-derived factor (SDF)-1alpha is expressed on dopaminergic (DA) neurones, but also on non-DA cells, suggesting presynaptic actions. Using whole-cell patch-clamp recordings in DA neurones of rat SN slices at a holding potential of -60 mV, we showed here that SDF-1alpha exerts multiple presynaptic effects. First, SDF-1alpha (10 nm) induced an increase in the frequency of spontaneous and miniature GABA(A) postsynaptic currents by presynaptic mechanisms, consistent with the presence of CXCR4 on GABAergic neurones of the SN, as revealed by immunocytochemistry. Second, SDF-1alpha (0.1-1 nm) induced a glutamatergic inward current resistant to tetrodotoxin (TTX), most probably the result of glutamate release from non-neuronal cells. This inward current was not blocked by the CXCR4 antagonist AMD 3100 (1 microm), consistent with the lack of CXCR4 on astrocytes as shown by immunocytochemistry under basal conditions. Finally, SDF-1alpha (10 nm) induced, via CXCR4, an outward G protein-activated inward rectifier (GIRK) current, which was TTX sensitive and prevented by application of the GABA(B) antagonist CGP55845A, suggesting GABA spillover on to GABA(B) receptors. Our results show that SDF-1alpha induces, via presynaptic mechanisms, alterations in the excitability of DA neurones as confirmed by current-clamp experiments.
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6097, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia-Antipolis, Valbonne 06560, France.
A
A
Guyon
D
D
Skrzydelsi
C
C
Rovère
W
W
Rostène
S Mélik
SM
Parsadaniantz
J L
JL
Nahon
D000818:Animals; D001596:Benzylamines; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism* / Q000494:pharmacology; D000080027:Cyclams; D004298:Dopamine / Q000378:metabolism*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000187:drug effects / Q000378:metabolism; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000494:pharmacology; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000378:metabolism; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D001596:Benzylamines; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C486264:Cxcr4 protein, rat; D000080027:Cyclams; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D018756:GABA Antagonists; D006571:Heterocyclic Compounds; D007473:Ion Channels; D019718:Receptors, CXCR4; D011963:Receptors, GABA-A; D026941:Sodium Channel Blockers; D018698:Glutamic Acid; C088327:plerixafor; D004298:Dopamine