Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity

The repellent semaphorin 3A (Sema3A) causes growth cone turning or collapse by triggering cytoskeletal rearrangements and detachment of adhesion sites. Growth cone detachment is dependent on eicosanoid activation of protein kinase C epsilon (PKCε), but the characterization of the phospholipase A(2) (PLA(2) ) that releases arachidonic acid (AA) for eicosanoid synthesis has remained elusive. Here, we show, in rat dorsal root ganglion (DRG) neurons, that Sema3A stimulates PLA(2) activity, that Sema3A-induced growth cone turning and collapse are dependent on the release of AA, and that the primary PLA(2) involved is the group IV α isoform (GIVA). Silencing GIVA expression renders growth cones resistant to Sema3A-induced collapse, and GIVA inhibition reverses Sema3A-induced repulsion into attraction. These studies identify a novel, early step in Sema3A-signaling and a PLA(2) necessary for growth cone repulsion and collapse.