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

Maria Risi, Diletta Cavezza, Giulia Torromino, Anita Capalbo, Xabier Bujanda Cundin, Rosaria Martino, Filomena Grazia Alvino, Attilio Iemolo, Luisa Speranza, Carla Perrone-Capano, Marianna Crispino, Carmine Cirillo, Alberto Luini, Francesca Sacco, Paolo Grumati and Elvira Leonibus ()
Additional contact information
Maria Risi: National Research Council (CNR)
Diletta Cavezza: National Research Council (CNR)
Giulia Torromino: National Research Council (CNR)
Anita Capalbo: Institute of Biochemistry and Cell Biology (IBBC)
Xabier Bujanda Cundin: Telethon Foundation
Rosaria Martino: Institute of Biochemistry and Cell Biology (IBBC)
Filomena Grazia Alvino: National Research Council (CNR)
Attilio Iemolo: National Research Council (CNR)
Luisa Speranza: National Research Council (CNR)
Carla Perrone-Capano: National Research Council (CNR)
Marianna Crispino: University of Naples Federico II
Carmine Cirillo: Telethon Foundation
Alberto Luini: Institute of Biochemistry and Cell Biology (IBBC)
Francesca Sacco: Telethon Foundation
Paolo Grumati: Telethon Foundation
Elvira Leonibus: National Research Council (CNR)

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract 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 the same pathway in the medial prefrontal cortex (mPFC) but inhibiting it in the striatum. This impairment, arising from mPFC-driven recruitment of inhibitory striatal parvalbumin interneurons, can be prevented by optogenetic inhibition of the mPFC-striatal pathway. Low doses of SKF 38393 also rescue WMC deficits in a schizophrenia mouse model. These results highlight the need for a systems pharmacology approach that considers complex brain interactions and intracellular signalling pathways, rather than isolated drug-receptor interactions, to develop memory-enhancing treatments.

Date: 2025
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DOI: 10.1038/s41467-025-57788-5

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