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

Abstract

Activation of the cAMP pathway is one of the common mechanisms underlying long‐term potentiation (LTP). In the Drosophila mushroom body, simultaneous activation of odour‐coding Kenyon cells (KCs) and reinforcement‐coding dopaminergic neurons 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 developed a system to electrophysiologically monitor both short‐term and long‐term synaptic plasticity at KC output synapses and demonstrated that they are indeed an exception in which activation of the cAMP–protein kinase A pathway induces LTD. Contrary to the prevailing model, our cAMP imaging found no evidence for synergistic action of dopamine and KC activity on cAMP synthesis. Furthermore, we found that forskolin‐induced cAMP increase alone was insufficient for plasticity induction; it additionally required simultaneous KC activation to replicate the presynaptic LTD induced by pairing with dopamine. On the other hand, activation of the cGMP pathway paired with KC activation induced slowly developing LTP, proving antagonistic actions of the two second‐messenger pathways predicted by behavioural study. Finally, KC subtype‐specific interrogation of synapses revealed 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 the unexpected convergence point of the cAMP pathway and neuronal activity, but also establishes the methods to address physiological mechanisms of synaptic plasticity in this important model. imageKey points Although presynaptic cAMP increase generally facilitates synapses, olfactory associative learning in Drosophila, which depends on dopamine and cAMP signalling genes, induces long‐term depression (LTD) at the mushroom body output synapses. By combining electrophysiology, pharmacology and optogenetics, we directly demonstrate that these synapses are an exception where activation of the cAMP–protein kinase A pathway leads to presynaptic LTD. Dopamine‐ or forskolin‐induced cAMP increase alone is not sufficient for LTD induction; neuronal activity, which has been believed to trigger cAMP synthesis in synergy with dopamine input, is required in the downstream pathway of cAMP. In contrast to cAMP, activation of the cGMP pathway paired with neuronal activity induces presynaptic long‐term potentiation, which explains behaviourally observed opposing actions of transmitters co‐released by dopaminergic neurons. Our work not only revises the role of cAMP in synaptic plasticity, but also provides essential methods to address physiological mechanisms of synaptic plasticity in this important model system.

The caloric value of food intake structurally adjusts a neuronal mushroom body circuit mediating olfactory learning inDrosophila

“…Furthermore, a comprehensive understanding of the physiological impact of the observed structural plasticity on synaptic transmission remains elusive. Recent reports indicate that increases in cAMP levels in addition with KC activation lead to synaptic depression, with temporal differences across KC compartments ( Yamada et al 2024 ), as is the case in aversive associative learning ( Hancock et al 2022 ). The decrease in synaptic connectivity might perhaps influence the generation of learning-induced synaptic depression.…”

Sensory encoding and memory in the mushroom body: signals, noise, and variability

“…The solution is twofold. First, cAMP production alone is not sufficient: A recent study showed that KCs require simultaneous cAMP production and KC depolarization in order to depress their presynaptic release probability ( Yamada et al 2024 ). Second, KCs form extensive axonal synapses with each other, as revealed in the connectome ( Eichler et al 2017 ; Takemura et al 2017 ; Li et al 2020 ).…”

“…NO activates soluble guanylate cyclase (sGC), which produces cGMP and triggers transcriptional changes that promote forgetting ( Takakura et al 2023 ). sGC activity slowly potentiates KC–MBON synapses, but, as with cAMP, only when the KC is simultaneously active with sGC ( Yamada et al 2024 ).…”