Temporally and Spatially Localized PKA Activity within Learning and Memory Circuitry Regulated by Network Feedback

Sears, James C.; Broadie, Kendal

doi:10.1523/eneuro.0450-21.2022

Cited by 3 publications

(1 citation statement)

References 59 publications

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“…To directly monitor the kinase activity levels of PKA, we expressed PKA activity reporter PKA.SPARK [74] in the mushroom body Kenyon cells driven by the mushroom bodyspecific VT30559-Gal4 (Figure 5B). Upon PKA activation, SPARK signal forms puncta from otherwise diffused signal in vitro and in vivo [74,75]. We indeed observed an increase in the number of PKA SPARK puncta in inc mutants, while the average level of SPARK intensity did not change (Figures 5C-5E).…”

Section: Mushroom Body Pka Kinase Activity Is Increased In Inc Mutantsmentioning

confidence: 51%

Cognitive hyperplasticity drives insomnia

Huang,

Piao,

Zhao

et al. 2024

Preprint

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Sleep is vital for maintenance of cognitive functions and lifespan across the animal kingdom. Here, we report our surprising findings that insomniac (inc)Drosophilashort sleep mutants, which lack a crucial adaptor protein for the autism-associated Cullin-3 ubiquitin ligase, exhibited excessive olfactory memory. Through a genetic modifier screen, we find that a mild attenuation of Protein Kinase A (PKA) signaling specifically rescued the sleep and longevity phenotypes ofincmutants. Surprisingly, this mild PKA signaling reduction further boosted the excessive memory inincmutants, coupled with further exaggerated mushroom body overgrowth phenotypes. We propose that an intrinsic hyperplasticity scenario genuine toincmutants enhances cognitive functions. Elevating PKA signaling seems to serve as a checkpoint which allows to constrain the excessive memory and mushroom body overgrowth in these animals, albeit at the sacrifice of sleep and longevity. Our data offer a mechanistic explanation for the sleep deficits ofincmutants, which challenges traditional views on the relation between sleep and memory, and suggest that behavioral hyperplasticity, e.g., prominent in autistic patients, can provoke sleep deficits.

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Section: Mushroom Body Pka Kinase Activity Is Increased In Inc Mutantsmentioning

confidence: 51%

Cognitive hyperplasticity drives insomnia

Huang,

Piao,

Zhao

et al. 2024

Preprint

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cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization

Ho,

Shaban,

Mahmood

et al. 2024

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

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Cytoplasmic mislocalization and aggregation of TDP-43 protein are hallmarks of amyotrophic lateral sclerosis (ALS) and are observed in the vast majority of both familial and sporadic cases. How these two interconnected processes are regulated on a molecular level, however, remains enigmatic. Genome-wide screens for modifiers of the ALS-associated genes TDP-43 and FUS have identified the phospholipase D (Pld) pathway as a key regulator of ALS-related phenotypes in the fruit fly Drosophila melanogaster [M. W. Kankel et al. , Genetics 215 , 747–766 (2020)]. Here, we report the results of our search for downstream targets of the enzymatic product of Pld, phosphatidic acid. We identify two conserved negative regulators of the cAMP/PKA signaling pathway, the phosphodiesterase dunce and the inhibitory subunit PKA-R2 , as modifiers of pathogenic phenotypes resulting from overexpression of the Drosophila TDP-43 ortholog TBPH . We show that knockdown of either of these genes results in a mitigation of both TBPH aggregation and mislocalization in larval motor neuron cell bodies, as well as an amelioration of adult-onset motor defects and shortened lifespan induced by TBPH. We determine that PKA kinase activity is downstream of both TBPH and Pld and that overexpression of the PKA target CrebA can rescue TBPH mislocalization. These findings suggest a model whereby increasing cAMP/PKA signaling can ameliorate the molecular and functional effects of pathological TDP-43.

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Cholesterol is required for activity-dependent synaptic growth

Shaheen,

Richter Gorey,

Sghaier

et al. 2023

Journal of Cell Science

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Changes in cholesterol content of neuronal membranes occur during development and brain aging. Little is known about whether synaptic activity regulates cholesterol levels in neuronal membranes and whether these changes affect neuronal development and function. We generated transgenic flies that express the cholesterol binding D4H domain of Perfringolysin O toxin and found increased levels of cholesterol in presynaptic terminals of Drosophila larval neuromuscular junctions following increased synaptic activity. Reduced cholesterol impaired synaptic growth and largely prevented activity-dependent synaptic growth. Presynaptic knockdown of adenylyl cyclase phenocopied the impaired synaptic growth caused by reducing cholesterol. Furthermore, the effects of knocking down adenylyl cyclase and reducing cholesterol were not additive, suggesting that they function in the same pathway. Increasing cAMP levels using a dunce mutant with reduced phosphodiesterase activity failed to rescue this impaired synaptic growth, suggesting that cholesterol functions downstream of cAMP. We used a PKA sensor to show that reducing cholesterol levels reduced presynaptic PKA activity. Collectively, our results demonstrate that enhanced synaptic activity increased cholesterol levels in presynaptic terminals and that these changes likely activate the cAMP-PKA pathway during activity-dependent growth.

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Temporally and Spatially Localized PKA Activity within Learning and Memory Circuitry Regulated by Network Feedback

Cited by 3 publications

References 59 publications

Cognitive hyperplasticity drives insomnia

Cognitive hyperplasticity drives insomnia

cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization

Cholesterol is required for activity-dependent synaptic growth

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