Dataset Information

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.

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Xabier Bujanda

LAB HEAD: Elvira De Leonibus

PROVIDER: PXD045107 | Pride | 2025-05-06

REPOSITORIES: Pride

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			Action	DRS
	2021-11-16_MS_DL_MDR_skftreatment_SKFHIGH_3210.raw	Raw
	2021-11-16_MS_DL_MDR_skftreatment_SKFHIGH_3215.raw	Raw
	2021-11-16_MS_DL_MDR_skftreatment_SKFHIGH_3219.raw	Raw
	2021-11-16_MS_DL_MDR_skftreatment_SKFHIGH_3302.raw	Raw
	2021-11-16_MS_DL_MDR_skftreatment_SKFLOW_3209.raw	Raw

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Cortico-striatal circuit mechanisms drive the effects of D1 dopamine agonists on memory capacity in mice through cAMP/PKA signalling.

De Risi Maria M Cavezza Diletta D Torromino Giulia G Capalbo Anita A Cundin Xabier Bujanda XB Di Martino Rosaria R Alvino Filomena Grazia FG Iemolo Attilio A Speranza Luisa L Perrone-Capano Carla C Crispino Marianna M Cirillo Carmine C Luini Alberto A Sacco Francesca F Grumati Paolo P De Leonibus Elvira E

Nature communications 20250317 1

Working memory capacity (WMC), the number of items remembered in a short-time interval, is regulated by fronto-striatal dopamine (DA) and is reduced in schizophrenia. We investigated how excessive and insufficient D1 dopamine receptor stimulation impairs and expands WMC, focusing on the cAMP/PKA pathway in the fronto-striatal circuit. Low doses of the D1 agonist SKF 38393 enhance WMC by activating the striatum (mice remember more objects), while high doses, paradoxically, impair WMC, activating ...[more]

PMID: 40097401

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Project description:The striatum is the main input structure of the basal ganglia, receiving information from the cortex and the thalamus and consisting of D1- and D2- medium spiny neurons (MSNs). D1-MSNs and D2-MSNs are essential for motor control and cognitive behaviors and have implications in Parkinson’s Disease. In the present study, we demonstrated that Sp9 positive progenitors produced both D1-MSNs and D2-MSNs and that Sp9 expression was rapidly downregulated in postmitotic D1-MSNs. Furthermore, we found that sustained Sp9 expression in lateral ganglionic eminence (LGE) progenitor cells and their descendants led to promoting D2-MSNs identity and repressing D1-MSNs identity during striatal development. As a result, sustained Sp9 expression resulted in an imbalance between D1-MSNs and D2-MSNs in the mouse striatum. In addition, the fate-changed D2 like-MSNs survived normally in adulthood. Taken together, our finding supported that Sp9 was sufficient to promote D2-MSNs identity and repress D1-MSNs identity, and Sp9 was a negative regulator of D1-MSNs fate. The striatum is the main input structure of the basal ganglia, receiving information from the cortex and the thalamus and consisting of D1- and D2- medium spiny neurons (MSNs). D1-MSNs and D2-MSNs are essential for motor control and cognitive behaviors and have implications in Parkinson’s Disease. In the present study, we demonstrated that Sp9 positive progenitors produced both D1-MSNs and D2-MSNs and that Sp9 expression was rapidly downregulated in postmitotic D1-MSNs. Furthermore, we found that sustained Sp9 expression in lateral ganglionic eminence (LGE) progenitor cells and their descendants led to promoting D2-MSNs identity and repressing D1-MSNs identity during striatal development. As a result, sustained Sp9 expression resulted in an imbalance between D1-MSNs and D2-MSNs in the mouse striatum. In addition, the fate-changed D2 like-MSNs survived normally in adulthood. Taken together, our finding supported that Sp9 was sufficient to promote D2-MSNs identity and repress D1-MSNs identity, and Sp9 was a negative regulator of D1-MSNs fate.