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

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 D₁ and D₃ receptors. Using in vivo microdialysis, we show that D₁ and D₃ 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 D₃R 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.