Stromal cell-derived factor-1α modulation of the excitability of rat substantia nigra dopaminergic neurones: presynaptic mechanisms.

In rat substantia nigra (SN), Chemokine (CXC motif) receptor 4 (CXCR 4) for the chemokine stromal cell-derived factor (SDF)-1α 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-1α exerts multiple presynaptic effects. First, SDF-1α (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-1α (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 µm), consistent with the lack of CXCR4 on astrocytes as shown by immunocytochemistry under basal conditions. Finally, SDF-1α (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-1α induces, via presynaptic mechanisms, alterations in the excitability of DA neurones as confirmed by current-clamp experiments. [ABSTRACT FROM AUTHOR]