Cortico-striatal circuit mechanisms drive the effects of D1 dopamine agonists on memory capacity in mice through cAMP/PKA signalling
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.
Authors
- Carla Perrone‐Capano (ORCID: https://orcid.org/0000-0002-6327-9753)
- Filomena Grazia Alvino
- Francesca Sacco (ORCID: https://orcid.org/0000-0001-5586-9529)
- Attilio Iemolo (ORCID: https://orcid.org/0000-0002-1102-7220)
- Elvira De Leonibus (ORCID: https://orcid.org/0000-0003-0220-2864)
- Rosaria Di Martino (ORCID: https://orcid.org/0000-0002-4877-3454)
- Anita Capalbo (ORCID: https://orcid.org/0000-0002-8399-4463)
- Alberto Luini (ORCID: https://orcid.org/0000-0002-8729-2549)
- Diletta Cavezza (ORCID: https://orcid.org/0000-0003-0696-6968)
- Paolo Grumati (ORCID: https://orcid.org/0000-0002-9942-9389)
- Carmine Cirillo (ORCID: https://orcid.org/0000-0002-1639-7677)
- Giulia Torromino (ORCID: https://orcid.org/0000-0002-7041-0289)
- Maria De Risi (ORCID: https://orcid.org/0000-0002-2741-6837)
- Luisa Speranza (ORCID: https://orcid.org/0000-0002-4018-6503)
- Marianna Crispino (ORCID: https://orcid.org/0000-0002-5797-8830)
- Xabier Bujanda Cundin (ORCID: https://orcid.org/0009-0004-4660-7251)
Institutions
- Institute of Genetics and Biophysics (IT)
- Telethon Institute Of Genetics And Medicine (IT)
- Fondazione Telethon (IT)
- National Research Council (IT)
- Institute of Cell Biology and Neurobiology (IT)
- University of Naples Federico II (IT)
- Sapienza University of Rome (IT)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-17
- DOI
- https://doi.org/10.1038/s41467-025-57788-5
- Citations
- 6
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 4.84
Funders
- Consiglio Nazionale delle Ricerche