A role for presynaptic NMDA receptors in hippocampal plasticity

摘要

The dopaminergic receptors control the availability of the NMDA receptor co-agonist D-serine to enable proper synaptic activity and cognitive function N-methyl-p-aspartate receptors (NMDARs) are critical for healthy brain development and functioning but are also involved in a variety of disorders. Their activation requires D-serine or glycine as a necessary co-agonist but we are still largely ignor- ing which physiological factors regulate their supply and function at synapses. Dopaminergic modulation of glutamatergic neu- rotransmission and in particular of NMDARs in the prefrontal cortex (PFC) plays an important role in the control of cogni- tive functions. Accordingly, disruption of fronto-cortical dopamine (DA)-glutamate cross-talk is a hallmark of several neuropsychiatric disorders, including schizophrenia. In addition, reduced availability of the co-agonist p-serine could be at the origin of the hypo- function of synaptic NMDA receptors (NMDARs) and therefore be central to the etiology of schizophrenia. Whether dopaminergic modulations of neuronal activity and cognitive functions involve p-serine is not known. Herein, we show that pharmacologically- and genetically-driven depletions of p-serine impair positive and negative modulations of glutamatergic transmission, neuronal excitability and plasticity by D; and D3-receptor activation, respec- tively. Furthermore, we report that the selective blockade of the D3-receptors increases global PFC activity and cognition in wild- type but not in null-mutant mice for serine racemase the enzyme that synthesizes p-serine. All these aberrant electrophysiological and behavioral signatures found in the mutant mice were fully alleviated when treating them with p-serine. Finally, we reveal that D;R and D3R activations coordinately regulate in opposite directions the extracellular levels of D-serine in the PFC and iden- tify the underlying signaling pathway. Collectively, our results reveal a key role for D-serine but not glycine in the neuro- modulation by dopamine of synaptic NMDARs functions, findings highly relevant to the etiology and treatment of schizophrenia but also to diseases where the dopamine-glutamate cross-talk is disrupted.