Details

Autor(en) / Beteiligte

• Dallérac, Glenn
• Li, Xia
• Lecouflet, Pierre
• Morisot, Nadège
• Sacchi, Silvia
• Asselot, Rachel
• Pham, Thu Ha
• Potier, Brigitte
• Watson, David J. G.
• Schmidt, Staffan
• Levasseur, Grégoire
• Fossat, Pascal
• Besedin, Andrey
• Rivet, Jean-Michel
• Coyle, Joseph T.
• Collo, Ginetta
• Pollegioni, Loredano
• Kehr, Jan
• Galante, Micaela
• Fone, Kevin C.
• Gardier, Alain M.
• Freret, Thomas
• Contarino, Angelo
• Millan, Mark J.
• Mothet, Jean-Pierre

Titel

Dopaminergic neuromodulation of prefrontal cortex activity requires the NMDA receptor coagonist d -serine

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2021-06, Vol.118 (23)

Ort / Verlag

Washington: National Academy of Sciences

Erscheinungsjahr

2021

Link zum Volltext

Quelle

EZB Free E-Journals

Beschreibungen/Notizen

• Significance Dopamine and glutamate in the prefrontal cortex are important substrates of higher cognitive functions, which are impaired in neuropsychiatric disorders. As regards glutamatergic pathways, a role for the NMDA receptor coagonist d -serine has been highlighted, yet its relationship to dopaminergic transmission remains unclear. In this study, we reveal that d -serine plays a pivotal role in the modulation by dopamine of NMDA receptor activity and cognitive performance in the prefrontal cortex. Comprehensive evidence for this interaction is provided at the synaptic, neuronal, network, and behavioral levels. These observations are of relevance to the pathophysiology and treatment of cognitive impairment in numerous disorders involving disruption of the frontocortical dialogue between dopamine and glutamate. Prefrontal control of cognitive functions critically depends upon glutamatergic transmission and N-methyl D-aspartate (NMDA) receptors, the activity of which is regulated by dopamine. Yet whether the NMDA receptor coagonist d -serine is implicated in the dopamine–glutamate dialogue in the prefrontal cortex (PFC) and other brain areas remains unexplored. Here, using electrophysiological recordings, we show that d -serine is required for the fine-tuning of glutamatergic neurotransmission, neuronal excitability, and synaptic plasticity in the PFC through the actions of dopamine at D 1 and D 3 receptors. Using in vivo microdialysis, we show that D 1 and D 3 receptors exert a respective facilitatory and inhibitory influence on extracellular levels and activity of d -serine in the PFC, with actions expressed primarily via the cAMP/protein kinase A (PKA) signaling cascade. Further, using functional magnetic resonance imaging (fMRI) and behavioral assessment, we show that d -serine is required for the potentiation of cognition by D 3 R blockade as revealed in a test of novel object recognition memory. Collectively, these results unveil a key role for d -serine in the dopaminergic neuromodulation of glutamatergic transmission and PFC activity, findings with clear relevance to the pathogenesis and treatment of diverse brain disorders involving alterations in dopamine–glutamate cross-talk.