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.

Time-dependent impact of glutamatergic modulators on the promnesiant effect of 5-HT6R blockade on mice recognition memory.

Selective antagonists at serotonin 5-HT6 receptors (5-HT6R) improve memory performance in rodents and are currently under clinical investigations. If blockade of 5-HT6R is known to increase glutamate release, only two studies have so far demonstrated an interaction between 5-HT6R and glutamate transmission, but both, using the non-competitive NMDA antagonist MK-801, insensitive to variations of glutamate concentrations. In a place recognition task, we investigated here in mice the role of glutamate transmission in the beneficial effects of 5-HT6R blockade (SB-271046). Through the use of increasing intervals (2, 4 and 6h) between acquisition and retrieval, we investigated the time-dependent impact of two different glutamatergic modulators. NMDAR-dependant glutamate transmission (NMDA Receptors) was either blocked by the competitive antagonist at NMDAR, CGS 19755, or potentiated by the glycine transporter type 1 (GlyT1) inhibitor, NFPS. Results showed that neither SB-271046, nor CGS 19755, nor NFPS, alter behavioural performances after short intervals, i.e. when control mice displayed significant memory performances (2h and 4h) (respectively 10, 3, and 0.625mg.kg-1). Conversely, with the 6h-interval, a situation in which spontaneous forgetting is observed in control mice, SB-271046 improved recognition memory performances. This beneficial effect was prevented when co-administered with either CGS 19755 or NFPS, which themselves had no effect. Interestingly, a dose-dependent effect was observed with NFPS, with promnesic effect observed at lower dose (0.156mg.kg-1) when administrated alone, whereas it did no modify promnesic effect of SB-271046. These results demonstrate that promnesiant effect induced by 5-HT6R blockade is sensitive to the competitive blockade of NMDAR and underline the need of a fine adjustment of the inhibition of GlyT1. Overall, our findings support the idea of a complex crosstalk between serotonergic and glutamatergic systems in the promnesic properties of 5-HT6R antagonists.

Deletion of the serotonin receptor type 7 disrupts the acquisition of allocentric but not egocentric navigation strategies in mice.

Spatial navigation is achieved through both egocentric (body-centered) and allocentric (externally-centered) strategies but decline with age, especially allocentric strategies. A better understanding of the neurobiological mechanisms underlying these strategies would allow the development of new treatments to mitigate this deterioration. Among them, the modulation of 5-HT7 receptor (5-HT7R) may constitute a potential strategy. Indeed, this receptor is known to play a role in spatial navigation, however its precise role in egocentric and allocentric strategies remains unclear. Here, we first examined the effect of 5-HT7 genetic invalidation (knock-out (KO) mice) in two versions of a water cross-maze task in which only egocentric or allocentric strategies were efficient to solve the task. Our results demonstrated that KO mice are able to learn an allocentric strategy. However, contrary to wild-type mice (WT mice), the acquisition rate was slower compared to the task requiring the acquisition of an egocentric strategy. Mice were then trained in a third version of the water maze, allowing the use of both egocentric and allocentric strategies. When facing conflicting spatial information, both KO and WT mice preferentially used an egocentric strategy. However, only WT mice displayed a greater latency to achieve the task. This suggests that WT mice are able to learn both information in parallel, but not KO mice (i.e. only learning an egocentric strategy). Altogether, these results provide evidence for the essential role of the 5HT7R in the acquisition of an allocentric strategy and in the ability to learn concomitantly both strategies.