Nitric oxide acts as a cotransmitter in a subset of dopaminergic neurons to diversify memory dynamics
- Janelia Research Campus, Howard Hughes Medical Institute, United States
- University of Virginia, United States
- Columbia University, United States
Abstract
Animals employ diverse learning rules and synaptic plasticity dynamics to record temporal and statistical information about the world. However, the molecular mechanisms underlying this diversity are poorly understood. The anatomically defined compartments of the insect mushroom body function as parallel units of associative learning, with different learning rates, memory decay dynamics and flexibility (Aso & Rubin 2016). Here we show that nitric oxide (NO) acts as a neurotransmitter in a subset of dopaminergic neurons in Drosophila. NO's effects develop more slowly than those of dopamine and depend on soluble guanylate cyclase in postsynaptic Kenyon cells. NO acts antagonistically to dopamine; it shortens memory retention and facilitates the rapid updating of memories. The interplay of NO and dopamine enables memories stored in local domains along Kenyon cell axons to be specialized for predicting the value of odors based only on recent events. Our results provide key mechanistic insights into how diverse memory dynamics are established in parallel memory systems.
Data availability
Complete transcript data were deposited to NCBI Gene Expression Omnibus (accession number GSE139889).
Article and author information
Author details
Ashok Litwin-Kumar
Funding
Howard Hughes Medical Institute
- Yoshinori Aso
- Robert P Ray
- Xi Long
- Daniel Bushey
- Teri-TB Ngo
- Brandi Sharp
- Christina Christoforou
- Amy Hu
- Andrew L Lemire
- Paul Tillberg
- Gerald M Rubin
National Institutes of Health (R01 GM84128)
- Karol Cichewicz
- Jay Hirsh
Simons Foundation (Global Brain)
- Yoshinori Aso
- Ashok Litwin-Kumar
- Gerald M Rubin
Burroughs Wellcome Foundation
- Ashok Litwin-Kumar
Gatsby Charitable Foundation
- Ashok Litwin-Kumar
National Science Foundation (DBI-1707398)
- Ashok Litwin-Kumar
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Aso et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Nitric oxide acts as a cotransmitter in a subset of dopaminergic neurons to diversify memory dynamics
eLife 8:e49257.
https://doi.org/10.7554/eLife.49257
Further reading
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- Neuroscience
The concept that dimeric protein complexes in synapses can sequentially replace their subunits has been a cornerstone of Francis Crick’s 1984 hypothesis, explaining how long-term memories could be maintained in the face of short protein lifetimes. However, it is unknown whether the subunits of protein complexes that mediate memory are sequentially replaced in the brain and if this process is linked to protein lifetime. We address these issues by focusing on supercomplexes assembled by the abundant postsynaptic scaffolding protein PSD95, which plays a crucial role in memory. We used single-molecule detection, super-resolution microscopy and MINFLUX to probe the molecular composition of PSD95 supercomplexes in mice carrying genetically encoded HaloTags, eGFP, and mEoS2. We found a population of PSD95-containing supercomplexes comprised of two copies of PSD95, with a dominant 12.7 nm separation. Time-stamping of PSD95 subunits in vivo revealed that each PSD95 subunit was sequentially replaced over days and weeks. Comparison of brain regions showed subunit replacement was slowest in the cortex, where PSD95 protein lifetime is longest. Our findings reveal that protein supercomplexes within the postsynaptic density can be maintained by gradual replacement of individual subunits providing a mechanism for stable maintenance of their organization. Moreover, we extend Crick’s model by suggesting that synapses with slow subunit replacement of protein supercomplexes and long-protein lifetimes are specialized for long-term memory storage and that these synapses are highly enriched in superficial layers of the cortex where long-term memories are stored.
