Interplay between 5-HT4 Receptors and GABAergic System within CA1 Hippocampal Synaptic Plasticity

International audienceThe type 4 serotonin receptor (5-HT4R) is highly involved in cognitive processes such as learning and memory. Behavioralstudies have shown a beneficial effect of its activation and conversely reported memory impairments by its blockade.However, how modulation of 5HT4R enables modifications of hippocampal synaptic plasticity remains elusive. To shed lighton the mechanisms at work, we investigated the effects of the 5-HT4R agonist RS67333 on long-term potentiation (LTP)within the hippocampal CA1 area. Although high-frequency stimulation-induced LTP remained unaffected by RS67333, themagnitude of LTP induced by theta-burst stimulation was significantly decreased. This effect was blocked by the selective5-HT4R antagonist RS39604. Further, 5-HT4R-induced decrease in LTP magnitude was fully abolished in the presence ofbicuculline, a GABAAR antagonist; hence, demonstrating involvement of GABA neurotransmission. In addition, we showedthat the application of a GABABR antagonist, CGP55845, mimicked the effect of 5-HT4R activation, whereas concurrentapplication of CGP55845 and RS67333 did not elicit an additive inhibition effect on LTP. To conclude, through investigation oftheta burst induced functional plasticity, we demonstrated an interplay between 5-HT4R activation and GABAergicneurotransmission within the hippocampal CA1 area

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