A midline switch of receptor processing regulates commissural axon guidance in vertebrates.

Commissural axon guidance requires complex modulations of growth cone sensitivity to midline-derived cues, but underlying mechanisms in vertebrates remain largely unknown. By using combinations of ex vivo and in vivo approaches, we uncovered a molecular pathway controlling the gain of response to a midline repellent, Semaphorin3B (Sema3B). First, we provide evidence that Semaphorin3B/Plexin-A1 signaling participates in the guidance of commissural projections at the vertebrate ventral midline. Second, we show that, at the precrossing stage, commissural neurons synthesize the Neuropilin-2 and Plexin-A1 Semaphorin3B receptor subunits, but Plexin-A1 expression is prevented by a calpain1-mediated processing, resulting in silencing commissural responsiveness. Third, we report that, during floor plate (FP) in-growth, calpain1 activity is suppressed by local signals, allowing Plexin-A1 accumulation in the growth cone and sensitization to Sema3B. Finally, we show that the FP cue NrCAM mediates the switch of Plexin-A1 processing underlying growth cone sensitization to Sema3B. This reveals pathway-dependent modulation of guidance receptor processing as a novel mechanism for regulating guidance decisions at intermediate targets.

Actions of propofol on substantia gelatinosa neurones in rat spinal cord revealed by in vitro and in vivo patch-clamp recordings.

Propofol, an intravenous general anaesthetic, exerts anaesthetic actions through interaction with gamma-aminobutyric acid type A (GABA(A)) receptors in the supraspinal nervous system. However, whether propofol has any significant effects on synaptic transmission at the spinal level and whether it exhibits antinociceptive action is still not fully clarified. Spontaneous activity and stimulus-evoked responses of substantia gelatinosa (SG) neurones to noxious pinch stimuli were recorded using spontaneously breathing rats under propofol anaesthesia using in vivo whole-cell patch-clamp techniques. Precise actions of propofol on GABAergic and glycinergic inhibitory postsynaptic currents (IPSCs) as well as excitatory postsynaptic currents (EPSCs) in SG neurones were also analyzed in spinal cord slice preparations. At clinical doses (5 mg/kg), propofol reversibly depressed action potentials elicited by noxious mechanical stimuli applied to the skin in the majority (6/8) of SG neurons recorded under in vivo conditions. This depression may have been caused by interactions of propofol with GABA(A) receptors, as decay time of GABAergic sIPSCs was prolonged after propofol injection (128 +/- 11% of control, n = 5) with minimal effect on EPSCs. Although prolongation of IPSCs in vivo was reversible, IPSCs were progressively prolonged even after washout of propofol when the effect was tested using spinal cord slices. Propofol had a mild depressant effect on Adelta- and C-afferent-mediated EPSCs. We conclude that systemic bolus injection of propofol reversibly depressed nociceptive transmission, at least in part, by enhancing postsynaptic GABA(A) receptor-mediated responses in the SG.