PKA regulation of neuronal function requires the dissociation of catalytic subunits from regulatory subunits DOI Creative Commons

Wei-Hong Xiong,

Maozhen Qin,

Haining Zhong

et al.

eLife, Journal Year: 2024, Volume and Issue: 13

Published: March 5, 2024

Protein kinase A (PKA) plays essential roles in diverse cellular functions. However, the spatiotemporal dynamics of endogenous PKA upon activation remain debated. The classical model predicts that catalytic subunits dissociate from regulatory presence cAMP, whereas a second proposes associated with following physiological activation. Here, we report different subtypes, as defined by subunit, exhibit distinct subcellular localization at rest CA1 neurons cultured hippocampal slices. Nevertheless, when all tested subtypes are activated norepinephrine, presumably via β-adrenergic receptor, translocate to dendritic spines but unmoved. These differential spatial between indicate least significant fraction dissociates. Furthermore, PKA-dependent regulation synaptic plasticity and transmission can be supported only wildtype, dissociable PKA, not inseparable PKA. results achieve function neurons.

Language: Английский

Unraveling the dynamics of dopamine release and its actions on target cells DOI Creative Commons
Tanya Sippy, Nicolas X. Tritsch

Trends in Neurosciences, Journal Year: 2023, Volume and Issue: 46(3), P. 228 - 239

Published: Jan. 10, 2023

Language: Английский

Citations

45
Adenosine signalling to astrocytes coordinates brain metabolism and function DOI Creative Commons
Shefeeq M. Theparambil, Olga Kopach, Alice Braga

et al.

Nature, Journal Year: 2024, Volume and Issue: 632(8023), P. 139 - 146

Published: July 3, 2024

Abstract Brain computation performed by billions of nerve cells relies on a sufficient and uninterrupted nutrient oxygen supply 1,2 . Astrocytes, the ubiquitous glial neighbours neurons, govern brain glucose uptake metabolism 3,4 , but exact mechanisms metabolic coupling between neurons astrocytes that ensure on-demand support neuronal energy needs are not fully understood 5,6 Here we show, using experimental in vitro vivo animal models, activity-dependent activation is mediated neuromodulator adenosine acting astrocytic A2B receptors. Stimulation receptors recruits canonical cyclic 3′,5′-monophosphate–protein kinase A signalling pathway, leading to rapid astrocyte release lactate, which supplements extracellular pool readily available substrates. Experimental mouse models involving conditional deletion gene encoding showed adenosine-mediated essential for maintaining synaptic function, especially under conditions high demand or reduced supply. Knockdown receptor expression led major reprogramming metabolism, prevented plasticity hippocampus, severely impaired recognition memory disrupted sleep. These data identify as an sensor activity show cAMP tunes its fundamental functions such sleep memory.

Language: Английский

Citations

43
Primary ciliary protein kinase A activity in the prefrontal cortex modulates stress in mice DOI
Jiajun Yang, Yingjie Dong, Jing Liu

et al.

Neuron, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

Citations

2
Neuronal activity-induced, equilibrative nucleoside transporter-dependent, somatodendritic adenosine release revealed by a GRAB sensor DOI Creative Commons
Zhaofa Wu, Yuting Cui, Huan Wang

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(14)

Published: March 30, 2023

The purinergic signaling molecule adenosine (Ado) modulates many physiological and pathological functions in the brain. However, exact source of extracellular Ado remains controversial. Here, utilizing a newly optimized genetically encoded GPCR-Activation-Based fluorescent sensor (GRABAdo), we discovered that neuronal activity-induced elevation is due to direct release from somatodendritic compartments neurons, rather than axonal terminals, hippocampus. Pharmacological genetic manipulations reveal depends on equilibrative nucleoside transporters but not conventional vesicular mechanisms. Compared with fast-vesicular glutamate release, slow (~40 s) requires calcium influx through L-type channels. Thus, this study reveals an activity-dependent second-to-minute local potentially serving modulatory as retrograde signal.

Language: Английский

Citations

42
Learning critically drives parkinsonian motor deficits through imbalanced striatal pathway recruitment DOI Creative Commons
T. H. C. Cheung, Yunmin Ding, Xiaoxi Zhuang

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(12)

Published: March 15, 2023

Dopamine (DA) loss in Parkinson’s disease (PD) causes debilitating motor deficits. However, dopamine is also widely linked to reward prediction and learning, the contribution of dopamine-dependent learning movements that are impaired PD—which often do not lead explicit rewards—is unclear. Here, we used two distinct tasks dissociate dopamine’s acute motoric effects vs. its long-lasting, learning-mediated effects. In dopamine-depleted mice, task performance gradually worsened with exposure. Task experience was critical, as mice remained home cage during same period were relatively unimpaired when subsequently probed on task. Repeated replacement treatments acutely rescued deficits induced long-term rescue persisted despite treatment withdrawal. Surprisingly, both parkinsonian decline specific, implicating learning. D1R activation potently consolidated into rescue. Conversely, reduced D2R decline. either or prevented decline, restored balanced direct indirect striatal pathways. These findings suggest reinforcement maintenance movements—even leading rewards—are fundamental functions provide potential mechanisms for hitherto unexplained “long-duration response” by dopaminergic therapies PD.

Language: Английский

Citations

31
Altered motor learning and coordination in mouse models of autism spectrum disorder DOI Creative Commons
Katherine R. Cording, Helen S. Bateup

Frontiers in Cellular Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: Nov. 8, 2023

Autism spectrum disorder (ASD) is a complex neurodevelopmental with increasing prevalence. Over 1,000 risk genes have now been implicated in ASD, suggesting diverse etiology. However, the diagnostic criteria for still comprise two major behavioral domains - deficits social communication and interaction, presence of restricted repetitive patterns behavior (RRBs). The RRBs associated ASD include both stereotyped movements other motor manifestations including changes gait, balance, coordination, skill learning. In recent years, striatum, primary input center basal ganglia, has these ASD-associated behaviors, due to striatum’s role action selection, learning, habit formation. Numerous mouse models mutations developed shown alterations ASD-relevant behaviors. One commonly used assay, accelerating rotarod, allows assessment basic coordination this corticostriatal-dependent task, mice walk on rotating rod that gradually increases speed. extended version engage striatal-dependent learning mechanisms optimize their routine stay longer periods. This review summarizes findings studies examining rotarod performance across range models, resulting implications involvement striatal circuits ASD-related While task not uniform there cohort show increased performance. A growing number suggest propensity learn fixed may reflect common enhancement corticostriatal drive subset ASD-risk genes.

Language: Английский

Citations

30
Transient cAMP production drives rapid and sustained spiking in brainstem parabrachial neurons to suppress feeding DOI
Jonnathan Singh Alvarado, Andrew Lutas,

Joseph C. Madara

et al.

Neuron, Journal Year: 2024, Volume and Issue: 112(9), P. 1416 - 1425.e5

Published: Feb. 27, 2024

Language: Английский

Citations

11
Cortico-basal ganglia plasticity in motor learning DOI Creative Commons
Richard H. Roth, Jun Ding

Neuron, Journal Year: 2024, Volume and Issue: 112(15), P. 2486 - 2502

Published: July 12, 2024

Language: Английский

Citations

9
Macrophage-derived CTSS drives the age-dependent disruption of the blood-CSF barrier DOI
Yifan Chen, Yifei Zhou, Yuchen Bai

et al.

Neuron, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

1
Pharmacology of Adenosine Receptors: Recent Advancements DOI Creative Commons
Fabrizio Vincenzi, Silvia Pasquini, Chiara Contri

et al.

Biomolecules, Journal Year: 2023, Volume and Issue: 13(9), P. 1387 - 1387

Published: Sept. 14, 2023

Adenosine receptors (ARs) are widely acknowledged pharmacological targets yet still underutilized in clinical practice. Their ubiquitous distribution almost all cells and tissues of the body makes them, on one hand, excellent candidates for numerous diseases, other intrinsically challenging to exploit selectively a site-specific manner. This review endeavors comprehensively depict substantial advancements witnessed recent years concerning development drugs that modulate ARs. Through preclinical research, it has become evident modulation ARs holds promise treatment including central nervous system disorders, cardiovascular metabolic conditions, inflammatory autoimmune cancer. The latest studies discussed herein shed light novel mechanisms through which exert control over pathophysiological states. They also introduce new ligands innovative strategies receptor activation, presenting compelling evidence efficacy along with implicated signaling pathways. Collectively, these emerging insights underscore promising trajectory toward harnessing therapeutic potential multifaceted targets.

Language: Английский

Citations

18