cAMP oscillations and retinal activity are permissive for ephrin signaling during the establishment of the retinotopic map.
Spontaneous activity generated in the retina is necessary to establish a precise retinotopic map, but the underlying mechanisms are poorly understood. We demonstrate here that neural activity controls ephrin-A-mediated responses. In the mouse retinotectal system, we show that spontaneous activity of the retinal ganglion cells (RGCs) is needed, independently of synaptic transmission, for the ordering of the retinotopic map and the elimination of exuberant retinal axons. Activity blockade suppressed the repellent action of ephrin-A on RGC growth cones by cyclic AMP (cAMP)-dependent pathways. Unexpectedly, the ephrin-A5-induced retraction required cAMP oscillations rather than sustained increases in intracellular cAMP concentrations. Periodic photo-induced release of caged cAMP in growth cones rescued the response to ephrin-A5 when activity was blocked. These results provide a direct molecular link between spontaneous neural activity and axon guidance mechanisms during the refinement of neural maps.
Nicol
Xavier
X
INSERM, U616, Hôpital Salpêtrière, 47 Blvd. de l'Hôpital, 75013 Paris, France.
Voyatzis
Sylvie
S
Muzerelle
Aude
A
Narboux-Nême
Nicolas
N
Südhof
Thomas C
TC
Miles
Richard
R
Gaspar
Patricia
P
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D004622:Embryo, Mammalian; D036386:Ephrin-A5 / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D020439:Growth Cones / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D051938:Munc18 Proteins / Q000172:deficiency; D009924:Organ Culture Techniques; D010507:Periodicity; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D012160:Retina / Q000166:cytology / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014795:Visual Pathways / Q000166:cytology / Q000502:physiology*
D036386:Ephrin-A5; D018691:Excitatory Amino Acid Antagonists; D051938:Munc18 Proteins; D010726:Phosphodiesterase Inhibitors; D011810:Quinoxalines; C497938:Stxbp1 protein, mouse; D013779:Tetrodotoxin; C056723:FG 9041; D000242:Cyclic AMP; D015056:1-Methyl-3-isobutylxanthine