Cyclic nucleotide-induced bidirectional long-term synaptic plasticity in Drosophila mushroom body

Activation of the cyclic adenosine monophosphate (cAMP) pathway generally facilitates synaptic transmission, serving as one of the common mechanisms underlying long-term potentiation (LTP). In the Drosophila mushroom body, simultaneous activation of odor-coding Kenyon cells (KCs) and reinforcement-coding dopaminergic neurons synergistically activates adenylyl cyclase in KC presynaptic terminals, which is believed to trigger synaptic plasticity underlying olfactory associative learning. However, learning induces long-term depression (LTD) at these synapses, contradicting the universal role of cAMP as a facilitator of transmission. Here, we develop a system to electrophysiologically monitor both short-term and long-term synaptic plasticity of KC output synapses and demonstrate that Drosophila mushroom body is indeed a rare, if not the only, exception where increase in cAMP level induces LTD. In contrary to the prevailing model, we find that cAMP increase alone is insufficient for plasticity induction; it additionally requires KC activation to replicate presynaptic LTD induced by pairing of dopamine and KC activation. On the other hand, activation of the cyclic guanosine monophosphate pathway paired with KC activation induces slowly developing LTP, proving antagonistic actions of the two second-messenger pathways predicted by behavioral study. Furthermore, subtype-specific interrogation of KC output synapses reveals that different KC subtypes exhibit distinct plasticity duration even among synapses on the same postsynaptic neuron. Thus, our work not only revises the role of cAMP in synaptic plasticity by uncovering unexpected convergence point of the cAMP pathway and neuronal activity, but also establishes the methods to address physiological mechanisms of synaptic plasticity in this historically important model system.