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AbstractActivation of the cAMP pathway is one of the common mechanisms underlying long‐term potentiation (LTP). In theDrosophilamushroom 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.image Key pointsAlthough presynaptic cAMP increase generally facilitates synapses, olfactory associative learning inDrosophila, 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.
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Dopamine-Dependent Plasticity Is Heterogeneously Expressed by Presynaptic Calcium Activity across Individual Boutons of the Drosophila Mushroom Body
Abstract TheDrosophilamushroom body (MB) is an important model system for studying the synaptic mechanisms of associative learning. In this system, coincidence of odor-evoked calcium influx and dopaminergic input in the presynaptic terminals of Kenyon cells (KCs), the principal neurons of the MB, triggers long-term depression (LTD), which plays a critical role in olfactory learning. However, it is controversial whether such synaptic plasticity is accompanied by a corresponding decrease in odor-evoked calcium activity in the KC presynaptic terminals. Here, we address this question by inducing LTD by pairing odor presentation with optogenetic activation of dopaminergic neurons (DANs). This allows us to rigorously compare the changes at the presynaptic and postsynaptic sites in the same conditions. By imaging presynaptic acetylcholine release in the condition where LTD is reliably observed in the postsynaptic calcium signals, we show that neurotransmitter release from KCs is depressed selectively in the MB compartments innervated by activated DANs, demonstrating the presynaptic nature of LTD. However, total odor-evoked calcium activity of the KC axon bundles does not show concurrent depression. We further conduct calcium imaging in individual presynaptic boutons and uncover the highly heterogeneous nature of calcium plasticity. Namely, only a subset of boutons, which are strongly activated by associated odors, undergo calcium activity depression, while weakly responding boutons show potentiation. Thus, our results suggest an unexpected nonlinear relationship between presynaptic calcium influx and the results of plasticity, challenging the simple view of cooperative actions of presynaptic calcium and dopaminergic input.
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- Award ID(s):
- 2034783
- PAR ID:
- 10469590
- Publisher / Repository:
- DOI PREFIX: 10.1523
- Date Published:
- Journal Name:
- eneuro
- Volume:
- 10
- Issue:
- 10
- ISSN:
- 2373-2822
- Format(s):
- Medium: X Size: Article No. ENEURO.0275-23.2023
- Size(s):
- Article No. ENEURO.0275-23.2023
- Sponsoring Org:
- National Science Foundation
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