Carbon monoxide, a retrograde messenger generated in post-synaptic mushroom body neurons evokes non-canonical dopamine release

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Dopaminergic neurons innervate extensive areas of the brain and release dopamine (DA) onto a wide range of target neurons. However, DA release is also precisely regulated, and in <jats:italic>Drosophila,</jats:italic> DA is released specifically onto mushroom body (MB) neurons, which have been coincidentally activated by cholinergic and glutamatergic inputs. The mechanism for this precise release has been unclear. Here we found that coincidentally activated MB neurons generate carbon monoxide (CO) which functions as a retrograde signal evoking local DA release from presynaptic terminals. CO production depends on activity of heme oxygenase in post-synaptic MB neurons, and CO-evoked DA release requires Ca<jats:sup>2+</jats:sup> efflux through ryanodine receptors in DA terminals. CO is only produced in MB areas receiving coincident activation, and removal of CO using scavengers blocks DA release. We propose that DA neurons utilize two distinct modes of transmission to produce global and local DA signaling.</jats:p><jats:sec><jats:title>SIGNIFICANCE STATEMENT</jats:title><jats:p>Dopamine (DA) is needed for various higher brain functions including memory formation. However, DA neurons form extensive synaptic connections, while memory formation requires highly specific and localized DA release. Here we identify a mechanism through which DA release from presynaptic terminals is controlled by postsynaptic activity. Postsynaptic neurons activated by cholinergic and glutamatergic inputs generate carbon monoxide, which acts as a retrograde messenger inducing presynaptic DA release. Released DA is required for memory-associated plasticity. Our work identifies a novel mechanism that restricts DA release to the specific postsynaptic sites that require DA during memory formation.</jats:p></jats:sec>

Pairing-dependent plasticity in a dissected fly brain is input-specific and requires synaptic CaMKII enrichment and nighttime sleep

“…Most of the previous studies investigating the associative learning circuit ex vivo have focused on mapping connectivity (Cohn et al, 2015;Barnstedt et al, 2016;Felsenberg et al, 2017;Felsenberg et al, 2018;Zhao et al, 2018) or characterizing a specific biochemical pathway (Tomchik and Davis, 2009;Handler et al, 2019;Ueno et al, 2020). Only a few ex vivo studies (Wang et al, 2008;Ueno et al, 2013;Suzuki-Sawano et al, 2017;Ueno et al, 2017) have focused on understanding MB circuit logic.…”

“…However, mechanistic studies employing the LTE paradigm reported no dopamine release after US pathway stimulation alone. Strong dopamine release was only seen after coincident activation of both the CS and the US pathways, and it was concluded that dopamine release is downstream of the CS+US coincidence and does not encode the primary US information (Ueno et al, 2017;Ueno et al, 2020). To directly address this discrepancy, we expressed a G-protein-coupled receptor-activation-based dopamine sensor (GRABDA) (Sun et al, 2020) in the KCs.…”