PI-3 kinase and IP3 are both necessary and sufficient to mediate NT3-induced synaptic potentiation

Signaling mechanisms underlying neurotrophic regulation of synaptic transmi ssion are not fully understood. Here we show that neurotrophin-3 (NT3)-indu ced potentiation of synaptic transmission at the neuromuscular synapses is blocked by inhibition of phosphoinositide-3 kinase, phospholipase C-gamma o r the downstream IP3 receptors of phospholipase C-gamma, but not by inhibit ion of MAP kinase. However, neither stimulation of Ca2+ release from intrac ellular stores by photolysis of caged IP3, nor expression of a constitutive ly active phosphoinositide-3 kinase (PI3K(star)) in presynaptic motoneurons alone is sufficient to enhance transmission. Photo-uncaging of IP3 in neur ons expressing PI3K(star) elicits a marked synaptic potentiation, mimicking the NT3 effect. These results reveal an involvement of PI3 kinase in trans mitter release, and suggest that concomitant activation of PI3 kinase and I P3 receptors is both necessary and sufficient to mediate the NTS-induced sy naptic potentiation.