PKA activation induces synapsin phosphorylation and diffusion along the axon. A–E, Hippocampal neurons were processed for double immunofluorescence with a phosphosite-1-specific anti-synapsin antibody (red) and an antibody that recognizes all synapsin isoforms (green). F, Neurons were stained with an anti-VAMP2 antibody (red) and a phosphosite-1-specific anti-synapsin antibody (green). Neurons were fixed in unstimulated conditions (A, A′) or after incubation with TTX (B, B′), H89 (C), forskolin (D, F), or forskolin plus KN93 (E). Under basal conditions, synapsin phosphorylation at site 1 can be detected in a subpopulation of synaptic boutons (arrowheads in A) as well as in growth cones (A′). Treatment of the neurons with TTX strongly reduces phosphorylation in nerve terminals (B) but not in growth cones (B′). Inhibition of PKA abolishes (C) whereas inhibition of CaM kinases only modestly decreases (E) synapsin phosphorylation. PKA activation induces site 1 phosphorylation and synapsin dispersion out of the terminals (D, F), whereas VAMP2 immunoreactivity remains confined to the synapses (F). G, Time-lapse experiment showing the dispersion of ECFP–SynI out of the synapses induced by forskolin (Forsk) and the recovery (Rec.) after removal of the drug. Scale bar: A, B, 10 μm; A′, B′, 15 μm; C–F, 20 μm; G, 5 μm.