PXD045107

PXD045107 is an original dataset announced via ProteomeXchange.

Title	Serial recruitment of protein kinase A in the striatum and in the prefrontal cortex mediates the inverted-U shaped dose-response curve of D1 agonists on memory capacity.
Description	This study investigates how D1 dopamine receptor agonists affect working memory capacity (WMC) in mice. WMC, the ability to remember a limited number of elements briefly (roughly 6 objects in humans and mice), is crucial for cognitive function and is impaired in schizophrenia. Dopamine, acting through D1 receptors in the medial prefrontal cortex (mPFC), supports working memory (WM). However, the use of D1 agonists as cognitive enhancers is limited by their “inverted U-shaped” dose-response pattern on WM, with low and high doses impairing it while moderate doses enhance it. Despite decades of pharmacological research, the mechanisms underlying this phenomenon remain unknown, limiting their clinical utility. Here we tested the hypothesis that D1 agonists impact WMC by activating the cAMP-dependent Protein Kinase (PKA) pathway differently in the frontal cortex and the striatum, where D1 receptors are highly concentrated. Phosphoproteomics analysis of the striatum uncovered distinct signaling pathways engaged by low and high doses of D1 agonists during memory retrieval. Using a combination of chemogenetics, pharmacological, and optogenetics approaches we show that the lower dose extends memory capacity beyond its normal limit by activating the cAMP/PKA pathway in the striatum, even rescuing WMC deficits in a schizophrenia model. Conversely, higher doses inhibit striatal activation and impair WMC by recruiting the same pathway in the mPFC. Optogenetic inhibition of glutamatergic input from the mPFC to the striatum mitigates the memory-impairing effects of the high-dose D1 agonist by limiting the recruitment of parvalbumin inhibitory interneurons. This study unveils a mechanism involving the reorganization of the fronto-striatal post-synaptic system that contributes to the "inverted U-shaped" dose-response curve observed with D1 agonists on WM, relevant for developing novel memory enhancers.
HostingRepository	PRIDE
AnnounceDate	2025-05-06
AnnouncementXML	Submission_2025-05-06_11:43:56.619.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Xabier Bujanda
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-09-05 06:43:55	ID requested
⏵ 1	2025-05-06 11:43:57	announced

De Risi M, Cavezza D, Torromino G, Capalbo A, Cundin XB, Di Martino R, Alvino FG, Iemolo A, Speranza L, Perrone-Capano C, Crispino M, Cirillo C, Luini A, Sacco F, Grumati P, De Leonibus E, Cortico-striatal circuit mechanisms drive the effects of D1 dopamine agonists on memory capacity in mice through cAMP/PKA signalling. Nat Commun, 16(1):2615(2025) [pubmed]

10.1038/s41467-025-57788-5;

ProteomeXchange project tag: Biology/Disease-Driven Human Proteome Project (B/D-HPP), Human Proteome Project

submitter keyword: dopamine, receptor D1,PKA

Elvira De Leonibus
contact affiliation	Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, Pozzuoli, Naples, Italy
contact email	deleonibus@tigem.it
lab head
Xabier Bujanda
contact affiliation	TELETHON INSTITUTE OF GENETICS AND MEDICINE
contact email	x.bujandac@tigem.it
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/05/PXD045107

PRIDE project URI

• PRIDE
  1. PXD045107
     1. Label: PRIDE project
     2. Name: Serial recruitment of protein kinase A in the striatum and in the prefrontal cortex mediates the inverted-U shaped dose-response curve of D1 agonists on memory capacity.