Null EPAC mutants reveal a sequential order of versatile cAMP effects during <i>Drosophila</i> aversive odor learning

Richlitzki, Antje; Latour, Philipp; Schwärzel, Martin

doi:10.1101/lm.043646.116

Cited by 5 publications

(4 citation statements)

References 37 publications

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“…Importantly, rescuing the expression of DopR or Rut-specifically in intrinsic MB neurons of otherwise mutant animals-restores normal olfactory learning and memory (7,10,(12)(13)(14)(15)(16)(17)(18). Further downstream, both Epac and PKA, as well as phosphorylation targets such as synapsin, have been shown to regulate learning and memory via effects in MB neurons (19)(20)(21)(22)(23). Thus, dopamine and cAMP are critical in intrinsic MB neurons for normal memory.…”

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confidence: 99%

Cyclic AMP-dependent plasticity underlies rapid changes in odor coding associated with reward learning

Louis

Stahl

Boto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Learning and memory rely on dopamine and downstream cAMP-dependent plasticity across diverse organisms. Despite the central role of cAMP signaling, it is not known how cAMP-dependent plasticity drives coherent changes in neuronal physiology that encode the memory trace, or engram. In , the mushroom body (MB) is critically involved in olfactory classical conditioning, and cAMP signaling molecules are necessary and sufficient for normal memory in intrinsic MB neurons. To evaluate the role of cAMP-dependent plasticity in learning, we examined how cAMP manipulations and olfactory classical conditioning modulate olfactory responses in the MB with in vivo imaging. Elevating cAMP pharmacologically or optogenetically produced plasticity in MB neurons, altering their responses to odorants. Odor-evoked Ca responses showed net facilitation across anatomical regions. At the single-cell level, neurons exhibited heterogeneous responses to cAMP elevation, suggesting that cAMP drives plasticity to discrete subsets of MB neurons. Olfactory appetitive conditioning enhanced MB odor responses, mimicking the cAMP-dependent plasticity in directionality and magnitude. Elevating cAMP to equivalent levels as appetitive conditioning also produced plasticity, suggesting that the cAMP generated during conditioning affects odor-evoked responses in the MB. Finally, we found that this plasticity was dependent on the Rutabaga type I adenylyl cyclase, linking cAMP-dependent plasticity to behavioral modification. Overall, these data demonstrate that learning produces robust cAMP-dependent plasticity in intrinsic MB neurons, which is biased toward naturalistic reward learning. This suggests that cAMP signaling may serve to modulate intrinsic MB responses toward salient stimuli.

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confidence: 99%

Cyclic AMP-dependent plasticity underlies rapid changes in odor coding associated with reward learning

Louis

Stahl

Boto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…These results complement previous findings demonstrating that β‐ARs stabilize divergent synaptic inputs through a mechanism requiring Epac signalling during heterosynaptic LTP (Brandwein & Nguyen, 2019). Recruitment of Epac during pairing of HFS with NE may simulate formation of memory with high salience, thereby triggering immediate encoding (Richlitzki, Latour, & Schwarzel, 2017).…”

Section: Discussionmentioning

confidence: 99%

Norepinephrine stabilizes translation‐dependent, homosynaptic long‐term potentiation through mechanisms requiring the cAMP sensor Epac, mTOR and MAPK

Maity

Chandanathil²,

Millis³

et al. 2020

Eur J of Neuroscience

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Neuromodulators regulate higher-order cognitive processes including learning and memory through modulation of synaptic transmission and plasticity. Norepinephrine is a neuromodulator that is secreted throughout the brain in response to novelty or increased arousal, which alters neural circuits by increasing the modifiability of CNS synapses. Norepinephrine activates metabotropic receptors, initiating complex intracellular signalling cascades that can promote enduring changes in synaptic strength including long-term potentiation (LTP). In particular, activation of beta-adrenergic receptors (β-ARs) by norepinephrine enhances LTP through downstream engagement of signalling cascades which upregulate protein synthesis at synapses. Here, we sought to determine the select signalling pathways recruited by norepinephrine to promote homosynaptic LTP at hippocampal synapses in mice. Application of norepinephrine initiated a long-lasting form of homosynaptic LTP that requires protein synthesis. Norepinephrine-mediated enhancement of LTP was reduced by inhibition of mammalian target of rapamycin and exchange protein directly activated by cAMP (Epac) but not cAMP-dependent protein kinase A, suggesting that the endogenous β-AR ligand norepinephrine may preferentially recruit Epac signalling to promote enduring changes in synaptic strength. These findings advance our understanding of the mechanisms through which norepinephrine regulates synaptic plasticity associated with formation of new memories.

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“…The Rap1 GEF EPAC is implicated in Malpighian tubule function ( Efetova et al. , 2013 ), in the role of mushroom body Kenyon cell neurons in aversive learning ( Richlitzki et al. , 2017 ), and in the response to anthrax toxin, via a role in blocking fusion of recycling endosomes with the plasma membrane ( Guichard et al.…”

Section: Introductionmentioning

confidence: 99%

Rap1 regulates apical contractility to allow embryonic morphogenesis without tissue disruption and acts in part via Canoe-independent mechanisms

Perez-Vale

Yow

Gurley

et al. 2023

MBoC

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Embryonic morphogenesis is powered by dramatic changes in cell shape and arrangement, driven by the cytoskeleton and its connections to adherens junctions. This requires robust linkage, allowing morphogenesis without disrupting tissue integrity. The small GTPase Rap1 is a key regulator of cell adhesion, controlling both cadherin-mediated and integrin-mediated processes. We have defined multiple roles in morphogenesis for one Rap1 effector, Canoe/Afadin, which ensures robust junction-cytoskeletal linkage. We now ask what mechanisms regulate Canoe and other junction-cytoskeletal linkers during Drosophila morphogenesis, defining roles for Rap1 and one of its guanine nucleotide exchange factor (GEF) regulators, Dizzy. Rap1 uses Canoe as one effector, regulating junctional planar polarity. However, Rap1 has additional roles in junctional protein localization and balanced apical constriction—in its absence, Bazooka/Par3 localization is fragmented, and cells next to mitotic cells apically constrict and invaginate, disrupting epidermal integrity. In contrast, the GEF Dizzy has phenotypes similar to but slightly less severe than Canoe loss, suggesting this GEF regulates Rap1 action via Canoe. Taken together, these data reveal that Rap1 is a crucial regulator of morphogenesis, likely acting in parallel via Canoe and other effectors, and that different Rap1 GEFs regulate distinct functions of Rap1.

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Null EPAC mutants reveal a sequential order of versatile cAMP effects during Drosophila aversive odor learning

Cited by 5 publications

References 37 publications

Cyclic AMP-dependent plasticity underlies rapid changes in odor coding associated with reward learning

Cyclic AMP-dependent plasticity underlies rapid changes in odor coding associated with reward learning

Norepinephrine stabilizes translation‐dependent, homosynaptic long‐term potentiation through mechanisms requiring the cAMP sensor Epac, mTOR and MAPK

Rap1 regulates apical contractility to allow embryonic morphogenesis without tissue disruption and acts in part via Canoe-independent mechanisms

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